Urea substituted imidazoquinolines

ABSTRACT

Imidazoquinoline and tetrahydroimidazoquinoline compounds that contain urea, thiourea, acylurea, or sulfonylurea functionality at the 1-position are useful as immune response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokines and are useful in the treatment of a variety of conditions including viral diseases and neoplastic diseases.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of U.S. application Ser. No.09/589,236, filed Jun. 7, 2000, now pending, which claims the benefit ofU.S. Ser. No. 60/138,365, filed Jun. 10, 1999.

FIELD OF THE INVENTION

This invention relates to imidazoquinoline compounds that have asubstituent at the 1-position containing urea, thiourea, acylurea orsulfonylurea functionality, to pharmaceutical compositions containingsuch compounds, and to pharmaceutical compositions containingimidazoquinoline compounds that have carbamate functionality at the1-position. A further aspect of this invention relates to the use ofthese compounds as immunomodulators, for inducing cytokine biosynthesisin animals, and in the treatment of diseases, including viral andneoplastic diseases.

BACKGROUND OF THE INVENTION

The first reliable report on the 1H-imidazo[4,5-c]quinoline ring system,Backman et al., J. Org. Chem. 15, 1278-1284 (1950) describes thesynthesis of1-(6-methoxy-8-quinolinyl)-2-methyl-1H-imidazo[4,5-c]quinoline forpossible use as an antimalarial agent. Subsequently, syntheses ofvarious substituted 1H-imidazo[4,5-c]quinolines were reported. Forexample, Jain et al., J. Med. Chem. 11, pp. 87-92 (1968), synthesizedthe compound 1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline as apossible anticonvulsant and cardiovascular agent. Also, Baranov et al.,Chem. Abs. 85, 94362 (1976), have reported several2-oxoimidazo[4,5-c]quinolines, and Berenyi et al., J. Heterocyclic Chem.18, 1537-1540 (1981), have reported certain2-oxoimidazo[4,5-c]quinolines.

Certain 1H-imidazo[4,5-c]quinolin-4-amines and 1- and 2-substitutedderivatives thereof were later found to be useful as antiviral agents,bronchodilators and immunomodulators. These are described in, interalia, U.S. Pat. Nos. 4,689,338; 4,698,348; 4,929,624; 5,037,986;5,268,376; 5,346,905; and 5,389,640, all of which are incorporatedherein by reference.

There continues to be interest in the imidazoquinoline ring system. Forexample, EP 894 797 describes imidazoquinoline type compounds that bearan amide containing substituent at the 1-position. The specification ofthis patent teaches that the active compounds of this series require aterminal amine substituent that may be incorporated into a heterocyclicring. As another example, WO 00/09506 describes imidazopyridine andimidazoquinoline compounds that may have an amide or urea containingsubstituent at the 1-position. The compounds described in thispublication as having utility contain a 1-substituent wherein the amideor urea nitrogen is part of a heterocyclic ring. Despite these attemptsto identify compounds that are useful as immune response modifiers,there is a continuing need for compounds that have the ability tomodulate the immune response, by induction of cytokine biosynthesis orother mechanisms.

SUMMARY OF THE INVENTION

We have found compounds that are useful in inducing cytokinebiosynthesis in animals. Accordingly, this invention providesimidazoquinoline and tetrahydroimidazoquinoline compounds of Formula(I):

wherein R₁, R₂, and R are as defined infra. The invention also providespharmaceutical compositions containing compounds of formula (Ia), whichcompounds have the same general structural formula as compounds (I)above.

The compounds of Formulae (I) and (Ia) are useful as immune responsemodifiers due to their ability to induce cytokine biosynthesis andotherwise modulate the immune response when administered to animals.This makes the compounds useful in the treatment of a variety ofconditions, e.g. viral diseases and tumors that are responsive to suchchanges in the immune response.

The invention further provides pharmaceutical compositions that containa therapeutically effective amount of a compound of Formula (I) or Ia),methods of inducing cytokine biosynthesis in an animal, treating a viralinfection in an animal, and/or treating a neoplastic disease in ananimal by administering a compound of Formula (I) or (Ia) to the animal.

In addition, methods of synthesizing the compounds of the invention andintermediates useful in the synthesis of these compounds are provided.

DETAILED DESCRIPTION OF THE INVENTION

As mentioned earlier, we have found that certain compounds inducecytokine biosynthesis in animals. Such compounds are represented byFormulae (I) and (Ia) below.

The invention provides compounds of Formula (I):

wherein

R₁ is -alkyl-NR₃—CY—NR₅—X—R₄ or -alkenyl-NR₃—CY—NR₅—X—R₄ wherein

Y is ═O or ═S;

X is a bond, —CO— or —SO₂—;

R₄ is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of whichmay be unsubstituted or substituted by one or more substituents selectedfrom the group consisting of:

-alkyl;

-alkenyl;

-aryl;

-heteroaryl;

-heterocyclyl;

-substituted aryl;

-substituted heteroaryl;

-substituted heterocyclyl;

—O-alkyl;

—O—(alkyl)₀₋₁-aryl;

—O—(alkyl)₀₋₁-substituted aryl;

—O—(alkyl)₀₋₁-heteroaryl;

—O—(alkyl)₀₋₁-substituted heteroaryl;

—O—(alkyl)₀₋₁-heterocyclyl;

—O—(alkyl)₀₋₁-substituted heterocyclyl;

—COOH;

—CO—O-alkyl;

—CO-alkyl;

—S(O)₀₋₂-alkyl;

—S(O)₀₋₂—(alkyl)₀₋₁-aryl;

—S(O)₀₋₂—(alkyl)₀₋₁-substituted aryl;

—S(O)₀₋₂—(alkyl)₀₋₁-heteroaryl;

—S(O)₀₋₂—(alkyl)₀₋₁-substituted heteroaryl;

—S(O)₀₋₂—(alkyl)₀₋₁-heterocyclyl;

—S(O)₀₋₂—(alkyl)₀₋₁-substituted heterocyclyl;

—(alkyl)₀₋₁—NR₃R₃;

—(alkyl)₀₋₁—NR₃—CO—O-alkyl;

—(alkyl)₀₋₁—NR₃—CO-alkyl;

—(alkyl)₀₋₁—NR₃—CO-aryl;

—(alkyl)₀₋₁—NR₃—CO-substituted aryl;

—(alkyl)₀₋₁—NR₃—CO-heteroaryl;

—(alkyl)₀₋₁—NR₃—CO-substituted heteroaryl;

—N₃;

-halogen;

-haloalkyl;

-haloalkoxy;

—CO-haloalkoxy;

—NO₂;

—CN;

—OH; and

—SH; and in the case of alkyl, alkenyl, or heterocyclyl, oxo; with theproviso that when X is a bond R₄ can additionally be hydrogen;

R₂ is selected from the group consisting of:

-hydrogen;

-alkyl;

-alkenyl;

-aryl;

-substituted aryl;

-heteroaryl;

-substituted heteroaryl;

-alkyl-O-alkyl;

-alkyl-O-alkenyl; and

-alkyl or alkenyl substituted by one or more substituents selected fromthe group consisting of:

—OH;

-halogen;

—N(R₃)₂;

—CO—N(R₃)₂;

—CO—C₁₋₀alkyl;

—CO—O—C₁₋₀alkyl;

—N₃;

-aryl;

-substituted aryl;

-heteroaryl;

-substituted heteroaryl;

-heterocyclyl;

-substituted heterocyclyl;

—CO-aryl;

—CO—(substituted aryl);

—CO-heteroaryl; and

—CO—(substituted heteroaryl);

each R₃ is independently selected from the group consisting of hydrogenand C₁₋₀ alkyl;

R₅ is selected from the group consisting of hydrogen and C₁₋₁₀ alkyl, orR₄ and R₅ can combine to form a 3 to 7 membered heterocyclic orsubstituted heterocyclic ring;

n is 0 to 4 and each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, halogen and trifluoromethyl, ora pharmaceutically acceptable salt thereof.

The invention also provides pharmaceutical compositions comprising atherapeutically effective amount of a compound of Formula (Ia):

wherein

R₁ is -alkyl-NR₃—CO—O—R₄ or -alkenyl-NR₃—CO—O—R₄;

R₄ is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of whichmay be unsubstituted or substituted by one or more substituents selectedfrom the group consisting of:

-alkyl;

-alkenyl;

-aryl;

-heteroaryl;

-heterocyclyl;

-substituted aryl;

-substituted heteroaryl;

-substituted heterocyclyl;

—O-alkyl;

—O—(alkyl)₀₋₁-aryl;

—O—(alkyl)₀₋₁-substituted aryl;

—O—(alkyl)₀₋₁-heteroaryl;

—O—(alkyl)₀₋₁-substituted heteroaryl;

—O—(alkyl)₀₋₁-heterocyclyl;

—O—(alkyl)₀₋₁-substituted heterocyclyl;

—COOH;

—CO—O-alkyl;

—CO-alkyl;

—S(O)₀₋₂-alkyl;

—S(O)₀₋₂—(alkyl)₀₋₁-aryl;

—S(O)₀₋₂—(alkyl)₀₋₁-substituted aryl;

—S(O)₀₋₂—(alkyl)₀₋₁-heteroaryl;

—S(O)₀₋₂—(alkyl)₀₋₁-substituted heteroaryl;

—S(O)₀₋₂—(alkyl)₀₋₁-heterocyclyl;

—S(O)₀₋₂—(alkyl)₀₋₁-substituted heterocyclyl;

—(alkyl)₀₋₁—NR₃R₃;

—(alkyl)₀₋₁—NR₃—CO—O-alkyl;

—(alkyl)₀₋₁—NR₃—CO-alkyl;

—(alkyl)₀₋₁—NR₃—CO-aryl;

—(alkyl)₀₋₁—NR₃—CO-substituted aryl;

—(alkyl)₀₋₁—NR₃—CO-heteroaryl;

—(alkyl)₀₋₁—NR₃—CO-substituted heteroaryl;

—N₃;

-halogen;

-haloalkyl;

-haloalkoxy;

—CO-haloalkoxy;

—NO₂;

—CN;

—OH; and

—SH; and in the case of alkyl, alkenyl, or heterocyclyl, oxo;

R₂ is selected from the group consisting of:

-hydrogen;

-alkyl;

-alkenyl;

-aryl;

-substituted aryl;

-heteroaryl;

-substituted heteroaryl;

-alkyl-O-alkyl;

-alkyl-O-alkenyl; and

-alkyl or alkenyl substituted by one or more substituents selected fromthe group consisting of:

—OH;

-halogen;

—N(R₃)₂;

—CO—N(R₃)₂;

—CO—C₁₋₁₀alkyl;

—CO—O—C₁₋₁₀alkyl;

—N₃;

-aryl;

-substituted aryl;

-heteroaryl;

-substituted heteroaryl;

-heterocyclyl;

-substituted heterocyclyl;

—CO-aryl;

—CO—(substituted aryl);

—CO-heteroaryl; and

—CO—(substituted heteroaryl);

each R₃ is independently selected from the group consisting of hydrogenand C₁₋₁₀ alkyl;

n is 0 to 4 and each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, halogen and trifluoromethyl, ora pharmaceutically acceptable salt thereof, in combination with apharmaceutically acceptable carrier.

Preparation of the Compounds

Imidazoquinolines of the invention can be prepared according to ReactionScheme I where R, R₁, R₂ and n are as defined above.

In step (1) of Reaction Scheme I a 4-chloro-3-nitroquinoline of FormulaII is reacted with an amine of Formula R₁NH₂ where R₁ is as definedabove to provide a 3-nitroquinolin-4-amine of Formula III. The reactioncan be carried out by adding amine to a solution of a compound ofFormula II in a suitable solvent such as chloroform or dichloromethaneand optionally heating. Many quinolines of Formula II are knowncompounds (see for example, U.S. Pat. No. 4,689,338 and references citedtherein).

In step (2) of Reaction Scheme I a 3-nitroquinolin-4-amine of FormulaIII is reduced to provide a quinoline-3,4-diamine of Formula IV.Preferably, the reduction is carried out using a conventionalheterogeneous hydrogentation catalyst such as platinum on carbon orpalladium on carbon. The reaction can conveniently be carried out on aParr apparatus in a suitable solvent such as isopropyl alcohol ortoluene.

In step (3) of Reaction Scheme I a quinoline-3,4-diamine of Formula IVis reacted with a carboxylic acid or an equivalent thereof to provide a1H-imidazo[4,5-c]quinoline of Formula V. Suitable equivalents tocarboxylic acid include acid halides, orthoesters, and 1,1-dialkoxyalkylalkanoates. The carboxylic acid or equivalent is selected such that itwill provide the desired R₂ substituent in a compound of Formula V. Forexample, triethyl orthoformate will provide a compound where R₂ ishydrogen and triethyl orthoacetate will provide a compound where R₂ ismethyl. The reaction can be run in the absence of solvent or in an inertsolvent such as toluene. The reaction is run with sufficient heating todrive off any alcohol or water formed as a byproduct of the reaction.

In step (4) of Reaction Scheme I a 1H-imidazo[4,5-c]quinoline of FormulaV is oxidized to provide a 1H-imidazo[4,5-c]quinoline-5N-oxide ofFormula VI using a conventional oxidizing agent that is capable offorming N-oxides. Preferred reaction conditions involve reacting asolution of a compound of Formula V in chloroform with3-chloroperoxybenzoic acid at ambient conditions.

In step (5) of Reaction Scheme I a 1H-imidazo[4,5-c]quinoline-5N-oxideof Formula VI is aminated to provide a 1H-imidazo[4,5-c]quinolin-4-amineof Formula VII, which is a subgenus of Formula I. Step (5) involves (i)reacting a compound of Formula VI with an acylating agent and then (ii)reacting the product with an aminating agent. Part (i) of step (5)involves reacting an N-oxide of Formula VI with an acylating agent.Suitable acylating agents include alkyl- or arylsulfonyl chlorides(e.g., benezenesulfonyl chloride, methanesulfonyl chloride,p-toluenesulfonyl chloride). Arylsulfonyl chlorides are preferred.Para-toluenesulfonyl chloride is most preferred. Part (ii) of step (5)involves reacting the product of part (i) with an excess of an aminatingagent. Suitable aminating agents include ammonia (e.g., in the form ofammonium hydroxide) and ammonium salts (e.g., ammonium carbonate,ammonium bicarbonate, ammonium phosphate). Ammonium hydroxide ispreferred. The reaction is preferably carried out by dissolving theN-oxide of Formula VI in an inert solvent such as dichloromethane,adding the aminating agent to the solution, and then slowly adding theacylating agent. The product or a pharmaceutically acceptable saltthereof can be isolated using conventional methods.

Alternatively, step (5) may be carried out by (i) reacting an N-oxide ofFormula VI with an isocyanate and then (ii) hydrolyzing the resultingproduct. Part (i) involves reacting the N-oxide with an isocyanatewherein the isocyanato group is bonded to a carbonyl group. Preferredisocyanates include trichloroacetyl isocyanante and aroyl isocyanatessuch as benzoyl isocyanate. The reaction of the isocyanate with theN-oxide is carried out under substantially anhydrous conditions byadding the isocyanate to a solution of the N-oxide in an inert solventsuch as chloroform or dichloromethane. Part (ii) involves hydrolysis ofthe product from part (i). The hydrolysis can be carried out byconventional methods such as heating in the presence of water or a loweralkanol optionally in the presence of a catalyst such as an alkali metalhydroxide or lower alkoxide.

Compounds of the invention where the R₁ substituent contains a urea or athiourea can also be prepared according to Reaction Scheme II where R,R₂, R₄ and n are as defined above and Y is O or S and m is an integerfrom 1 to 20.

In Reaction Scheme II an aminoalkyl substituted1H-imidazo[4,5-c]quinolin-4-amine of Formula VIII is reacted with anisocyanate or thioisocyanate of Formula IX to provide a compound ofFormula X which is a subgenus of Formula I. The reaction can be carriedout by adding a solution of the (thio)isocyanate in a suitable solventsuch as dichloromethane to a solution of a compound of Formula VIII,optionally at a reduced temperature. Many1H-imidazo[4,5-c]quinolin-4-amines of Formula VIII are known compounds(see for example U.S. Pat. No. 6,069,149 (Nanba)); others can be readilyprepared using known synthetic methods. Many isocyanates andthioisocyanates of Formula IX are commercially available; others can bereadily prepared using known synthetic methods.

The product or a pharmaceutically acceptable salt thereof can beisolated using conventional methods.

Compounds of the invention where the R₁ substituent contains a urea canalso be prepared according to Reaction Scheme III where R, R₂, R₄, R₅and n are as defined above and m is an integer from 1 to 20.

In Reaction Scheme III an aminoalkyl substituted1H-imidazo[4,5-c]quinolin-4-amine of Formula VIII is reacted with acarbamoyl chloride of Formula XI to provide a compound of Formula XIIwhich is a subgenus of Formula I. The reaction can be carried out byadding a solution of the carbamoyl chloride in a suitable solvent suchas pyridine to a solution of a compound of Formula VIII at ambienttemperature. Some carbamoyl chlorides of Formula XI are commerciallyavailable; others can be readily prepared using known synthetic methods.The product or a pharmaceutically acceptable salt thereof can beisolated using conventional methods.

Compounds of the invention where the R₁ substituent contains a carbamatecan also be prepared according to Reaction Scheme IV where R, R₂, R₄, nand m are as defined above.

In Reaction Scheme IV an aminoalkyl substituted1H-imidazo[4,5-c]quinolin-4-amine of Formula VIII is reacted with anchloroformate of Formula XIII to provide a compound of Formula XIV whichis a subgenus of Formula Ia. The reaction can be carried out by adding asolution of the chloroformate in a suitable solvent such asdichloromethane or pyridine to a solution of a compound of Formula VIIIoptionally at a reduced temperature. Many chloroformates of Formula XIIIare commercially available; others can be readily prepared using knownsynthetic methods. The product or a pharmaceutically acceptable saltthereof can be isolated using conventional methods.

Compounds of the invention where the R₁ substituent contains an acylurea can also be prepared according to Reaction Scheme V where R, R₂,R₄, n and m are as defined above.

In Reaction Scheme V an aminoalkyl substituted1H-imidazo[4,5-c]quinolin-4-amine of Formula VIII is reacted with anacyl isocyanate of Formula XV to provide a compound of Formula XVI whichis a subgenus of Formula I. The reaction can be carried out by adding asolution of the acyl isocyanate in a suitable solvent such asdichloromethane to a solution of a compound of Formula VIII at a reducedtemperature. Some acyl isocyanates of Formula XV are commerciallyavailable; others can be readily prepared using known synthetic methods.The product or a pharmaceutically acceptable salt thereof can beisolated using conventional methods.

Compounds of the invention where the R₁ substituent contains a sulfonylurea can also be prepared according to Reaction Scheme VI where R, R₂,R₄, n and m are as defined above.

In Reaction Scheme VI an aminoalkyl substituted1H-imidazo[4,5-c]quinolin-4-amine of Formula VIII is reacted with asulfonyl isocyanate of Formula XVII to provide a compound of FormulaXVIII which is a subgenus of Formula I. The reaction can be carried outby adding a solution of the sulfonyl isocyanate in a suitable solventsuch as dichloromethane to a solution of a compound of Formula VIII,optionally at a reduced temperature. Some sulfonyl isocyanates ofFormula XVII are commercially available; others can be readily preparedusing known synthetic methods. The product or a pharmaceuticallyacceptable salt thereof can be isolated using conventional methods.

Tetrahydroimidazoquinolines of the invention can be prepared accordingto Reaction Scheme VII where R₂, R₃, R₄, R₅, X, Y and m are as definedabove.

In step (1) of Reaction Scheme VII an aminoalkyl substituted1H-imidazo[4,5-c]quinolin-4-amine of Formula XIX is reduced to providean aminoalkyl substituted6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine of Formula XX.Preferably the reduction is carried out by suspending or dissolving thecompound of Formula XIX in trifluoroacetic acid, adding a catalyticamount of platinum (IV) oxide, and then subjecting the mixture tohydrogen pressure. The reaction can conveniently be carried out on aParr apparatus. The product or a salt thereof can be isolated usingconventional methods.

Step (2) of Reaction Scheme VII can be carried out using the methodsdescribed in Reaction Schemes II, III, IV, V and VI to provide acompound of Formula XXI which is a subgenus of Formula I.

Tetrahydroimidazoquinolines of the invention can also be preparedaccording to Reaction Scheme VIII where R, R₂, R₃, R₄, R₅, X, Y, n and mare as defined above.

In step (1) of Reaction Scheme VIII a6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolinyl tert-butylcarbamate ofFormula XXII is hydrolyzed to provide an aminoalkyl substituted6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine of Formula XXIII.The reaction can be carried out by dissolving the compound of FormulaXXII in a mixture of trifluoroacetic acid and acetonitrile and stirringat ambient temperature. Alternatively, the compound of Formula XXII canbe combined with dilute hydrochloric acid and heated on a steam bath.Tetrahydro-1H-imidazo[4,5-c]quinolinyl tert-butylcarbamates of FormulaXXII can be prepared using the synthetic route disclosed in U.S. Pat.No. 5,352,784 (Nikolaides). The product or a salt thereof can beisolated using conventional methods.

Step (2) of Reaction Scheme VIII can be carried out using the methodsdescribed in Reaction Schemes II, III, IV, V and VI to provide acompound of Formula XXIV which is a subgenus of Formula I.

Some compounds of Formula I can be readily prepared from other compoundsof Formula I. For example, compounds wherein the R₄ substituent containsa chloroalkyl group can be reacted with an amine to provide an R₄substituent substituted by a secondary or teriary amino group; compoundswherein the R₄ substituent contains a nitro group can be reduced toprovide a compound wherein the R₄ substituent contains a primary amine.

As used herein, the terms “alkyl”, “alkenyl”, “alkynyl” and the prefix“-alk” are inclusive of both straight chain and branched chain groupsand of cyclic groups, i.e. cycloalkyl and cycloalkenyl. Unless otherwisespecified, these groups contain from 1 to 20 carbon atoms, with alkenyland alkynyl groups containing from 2 to 20 carbon atoms. Preferredgroups have a total of up to 10 carbon atoms. Cyclic groups can bemonocyclic or polycyclic and preferably have from 3 to 10 ring carbonatoms. Exemplary cyclic groups include cyclopropyl, cyclopentyl,cyclohexyl and adamantyl.

The term “haloalkyl” is inclusive of groups that are substituted by oneor more halogen atoms, including groups wherein all of the availablehydrogen atoms are replaced by halogen atoms. This is also true ofgroups that include the prefix “haloalkyl-”. Examples of suitablehaloalkyl groups are chloromethyl, trifluoromethyl, and the like.

The term “aryl” as used herein includes carbocyclic aromatic rings orring systems. Examples of aryl groups include phenyl, naphthyl,biphenyl, fluorenyl and indenyl. The term “heteroaryl” includes aromaticrings or ring systems that contain at least one ring hetero atom (e.g.,O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl,quinolinyl, tetrazolyl, imidazo, pyrazolo, oxazolo, thiazolo and thelike.

“Heterocyclyl” includes non-aromatic rings or ring systems that containat least one ring hetero atom (e.g., O, S, N). Exemplary heterocyclicgroups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl,thiomorpholinyl, piperdinyl, piperazinyl, thiazolidinyl, imidazolidinyland the like.

Unless otherwise specified, the terms “substituted aryl”, “substitutedheteroaryl” and “substituted heterocyclyl” indicate that the rings orring systems in question are further substituted by one or moresubstituents independently selected from the group consisting of alkyl,alkoxy, alkylthio, hydroxy, halogen, haloalkyl, haloalkylcarbonyl,haloalkoxy (e.g., trifluoromethoxy), nitro, alkylcarbonyl,alkenylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocycloalkyl, nitrile,alkoxycarbonyl, alkanoyloxy, alkanoylthio, and in the case ofheterocyclyl, oxo.

In structural formulas representing compounds of the invention certainbonds are represented by dashed lines. These lines mean that the bondsrepresented by the dashed line can be present or absent. Accordingly,compounds of Formula I can be either imidazoquinoline compounds ortetrahydroimidazoquinoline compounds.

The invention is inclusive of the compounds described herein in any oftheir pharmaceutically acceptable forms, including isomers such asdiastereomers and enantiomers, salts, solvates, polymorphs, and thelike.

Pharmaceutical Compositions and Biological Activity

Pharmaceutical compositions of the invention contain a therapeuticallyeffective amount of a compound of the invention in combination with apharmaceutically acceptable carrier.

The term “a therapeutically effective amount” means an amount of thecompound sufficient to induce a therapeutic effect, such as cytokineinduction, antitumor activity and/or antiviral activity. Although theexact amount of active compound used in a pharmaceutical composition ofthe invention will vary according to factors known to those of skill inthe art, such as the physical and chemical nature of the compound aswell as the nature of the carrier and the intended dosing regimen, it isanticipated that the compositions of the invention will containsufficient active ingredient to provide a dose of about 100 ng/kg toabout 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg, of thecompound to the subject. Any of the conventional dosage forms may beused, such as tablets, lozenges, parenteral formulations, syrups,creams, ointments, aerosol formulations, transdermal patches,transmucosal patches and the like.

The compounds of the invention can be administered as the singletherapeutic agent in a treatment regimen, or the compounds of theinvention may be administered in combination with one another or withother active agents, including additional immune response modifiers,antivirals, antibiotics, and so on.

The compounds of the invention have been shown to induce the productionof certain cytokines in experiments performed according to the tests setforth below. These results indicate that the compounds are useful asimmune response modifiers that can modulate the immune response in anumber of different ways, rendering them useful in the treatment of avariety of disorders.

Cytokines that maybe induced by the administration of compoundsaccording to the invention generally include interferon (IFN) and/ortumor necrosis factor-α (TNF-α) as well as certain interleukins (IL).Cytokines whose biosynthesis may be induced by compounds of theinvention include IFN-α, TNF-α, IL-1, 6, 10 and 12, and a variety ofother cytokines. Among other effects, cytokines inhibit virus productionand tumor cell growth, making the compounds useful in the treatment oftumors and viral diseases.

In addition to the ability to induce the production of cytokines, thecompounds of the invention affect other aspects of the innate immuneresponse. For example, natural killer cell activity may be stimulated,an effect that may be due to cytokine induction. The compounds may alsoactivate macrophages, which in turn stimulates secretion of nitric oxideand the production of additional cytokines. Further, the compounds maycause proliferation and differentiation of B-lymphocytes.

Compounds of the invention also have an effect on the acquired immuneresponse. For example, although there is not believed to be any directeffect on T cells or direct induction of T cell cytokines, theproduction of the T helper type 1 (Th 1) cytokine IFN-γ is inducedindirectly and the production of the T helper type 2 (Th2) cytokinesIL-4, IL-5 and IL-13 are inhibited upon administration of the compounds.This activity means that the compounds are useful in the treatment ofdiseases where upregulation of the Th1 response and/or downregulation ofthe Th2 response is desired. In view of the ability of compounds ofFormula Ia to inhibit the Th2 immune response, the compounds areexpected to be useful in the treatment of conditions that are associatewith overstimulation of a Th2 response such as atopic diseases, e.g.,atopic dermatitis; asthma; allergy; allergic rhinitis; systemic lupuserythematosis; as a vaccine adjuvant for cell mediated immunity; andpossibly as a treatment for recurrent fungal diseases, periodontitis andchlamydia.

The immune response modifying effects of the compounds make them usefulin the treatment of a wide variety of conditions. Because of theirability to induce the production of cytokines such as IFN-α and/orTNF-α, and IL-12, the compounds are particularly useful in the treatmentof viral diseases and tumors. This immunomodulating activity suggeststhat compounds of the invention are useful in treating diseases such as,but not limited to, viral diseases including genital warts; commonwarts; plantar warts; Hepatitis B; Hepatitis C; Herpes Simplex Type Iand Type II; molluscum contagiosum; HIV; CMV; VZV; intraepithelialneoplasias such as cervical intraepithelial neoplasia; humanpapillomavirus (HPV) and associated neoplasias; fungal diseases, e.g.candida, aspergillus, and cryptococcal meningitis; neoplastic diseases,e.g., basal cell carcinoma, hairy cell leukemia, Kaposi's sarcoma, renalcell carcinoma, squamous cell carcinoma, myelogenous leukemia, multiplemyeloma, melanoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma,and other cancers; parasitic diseases, e.g. pneumocystis carnii,cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection,and leishmaniasis; and bacterial infections, e.g., tuberculosis, andmycobacterium avium. Additional diseases or conditions that can betreated using the compounds of the invention include eczema;eosinophilia; essential thrombocythaemia; leprosy; multiple sclerosis;Ommen's syndrome; discoid lupus; Bowen's disease; Bowenoid papulosis;and to enhance or stimulate the healing of wounds, including chronicwounds.

Accordingly, the invention provides a method of inducing cytokinebiosynthesis in an animal comprising administering an effective amountof a compound of Formula Ia to the animal. An amount of a compoundeffective to induce cytokine biosynthesis is an amount sufficient tocause one or more cell types, such as monocytes, macrophages, dendriticcells and B-cells to produce an amount of one or more cytokines such as,for example, IFN-β, TNF-β, IL-1,6,10 and 12 that is increased over thebackground level of such cytokines. The precise amount will varyaccording to factors known in the art but is expected to be a dose ofabout 100 ng/kg to about 50 mg/kg, preferably about 10 μg/kg to about 5mg/kg. The invention also provides a method of treating a viralinfection in an animal comprising administering an effective amount of acompound of Formula Ia to the animal. An amount effective to treat orinhibit a viral infection is an amount that will cause a reduction inone or more of the manifestations of viral infection, such as virallesions, viral load, rate of virus production, and mortality as comparedto untreated control animals. The precise amount will vary according tofactors known in the art but is expected to be a dose of 100 ng/kg toabout 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg. An amounteffective to treat a neoplastic condition is an amount that will cause areduction in tuor size or in the number of tumor foci. Again, theprecise amount will vary according to factors known in the art but isexpected to be a dose of about 100 mg/kg to about 50 mg/kg. Preferablyabout 10 mg/kg to about 5 mg/kg.

The invention is further described by the following examples, which areprovided for illustration only and are not intended to be limiting inany way.

EXAMPLE 1 tert-ButylN-[2-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate

Part A

Triethylamine (66.8 g, 0.33 mol) was added to a solution of tert-butylN-(2-aminoethyl)carbamate (55.0 g, 0.34 mol) in anhydrousdichloromethane (500 mL). 4-Chloro-3-nitroquinoline (68.2 g, 0.33 mol)was slowly added and the reaction exothermed. The reaction mixture wasallowed to stir at ambient temperature overnight. The resultingprecipitate was isolated by filtration to provide product as a yellowsolid. The filtrate was washed with water, dried over magnesium sulfateand then concentrated under vacuum. The resulting residue was slurriedwith hexane and filtered to provide additional product as a yellowsolid. The two crops were combined to provide 101 g of tert-butylN-[2-(3-nitroquinolin-4-yl)aminoethyl]carbamate as a yellow solid, m.p.157-158.

Part B

Platinum on carbon (1 g of 10%) and sodium sulfate (2 g) were added to aslurry of tert-butyl N-[2-(3-nitroquinolin-4-yl)aminoethyl]carbamate(100 g, 0.30 mol) in toluene (500 mL). The mixture was placed under ahydrogen atmosphere at 50 psi (3.4×10⁴ pascals) on a Parr apparatus atambient temperature overnight. The reaction mixture was filtered. Thefiltrate was concentrated to provide 73 g of tert-butylN-[2-(3-aminoquinolin-4-yl)aminoethyl]carbamate as a dark gold oil.

Part C

Triethyl orthoformate (11.3 g, 73.4 mmol) was added to a solution oftert-butyl N-[2-(3-aminoquinolin-4-yl)aminoethyl]carbamate (21 g, 69.4mmol) in anhydrous toluene (250 mL). The reaction mixture was heated atreflux for 5 hours and then allowed to slowly cool to ambienttemperature. The resulting precipitate was isolated by filtration anddried to provide 17.6 g of tert-butylN-[2-(1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate as a light tansolid, m.p. 154-155° C.

Part D

3-Chloroperoxybenzoic acid (17.4 g, 60.6 mmol) was added in smallportions to a solution of tert-butylN-[2-(1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (17.2 g, 55.1 mmol)in chloroform (250 mL). The reaction was maintained at ambienttemperature overnight and then quenched with 5% sodium carbonatesolution. The layers were separated. The organic layer was dried overmagnesium sulfate and then concentrated under vacuum to provide 15.0 gof 1-[2-(tert-butylcarbamyl)ethyl]-1H-imidazo[4,5-c]quinoline-5N-oxideas an off white solid, m.p. 213-215° C.

Part E

Trichloroacetyl isocyanate (9.5 g, 50.2 mmol) was slowly added to astirred solution of1-[2-(tert-butylcarbamyl)ethyl]-1H-imidazo[4,5-c]quinoline-5N-oxide(15.0 g, 45.7 mmol) in chloroform (200 mL). After 2 hours the reactionwas quenched with concentrated ammonium hydroxide (100 mL). Water (100mL) was added and the layers were separated. The aqueous layer wasextracted with chloroform. The organic layers were combined, dried overmagnesium sulfate and then concentrated under vacuum to provide a whitesolid. This material was slurried in warm methyl acetate and thenfiltered to provide 15 g of tert-butylN-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate as a whitesolid, m.p. 215° C. ¹H NMR (500 MHz, DMSO-d₆) δ 8.13 (t, J=8.0 Hz, 1H),8.03 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.23 (t,J=8.0 Hz, 1H), 7.06 (t, J=6.0 Hz, 1H), 6.56 (broad s, 2H), 4.63 (t,J=7.0 Hz, 2H), 3.43 (q, J=6.0 Hz, 2H), 1.32 (s, 9H); MS (EI) m/e327.1696 (327.1695 calcd for C₁₇H₂₁N₅O₂)

EXAMPLE 2 tert-ButylN-[2-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate

Part A

Using the general method of Example 1 Part A, tert-butylN-(4-aminobutyl)carbamate (254 g, 1.35 mol) was reacted with4-chloro-3-nitroquinoline hydrochloride (331 g, 1.35 mmol) to provide486 g of tert-butyl N-(4-[(3-nitroquinolin-4-yl)amino]butyl)carbamate asyellow solid. Analysis: Calculated for C₁₈H₂₄N₄O₄: %C, 59.99; %H, 6.71;%N, 15.55; Found: %C, 59.68; %H, 6.59; %N, 15.74.

Part B

Using the general method of Example 1 Part B, tert-butylN-(4-[(3-nitroquinolin-4-yl)amino]butyl)carbamate (162.6 g, 0.451 mol)was hydrogenated to provide 149 g of tert-butylN-(4-[(3-aminoquinolin-4-yl)amino]butyl)carbamate as a dark gold gum.

Part C

Using the general method of Example 1 Part C, tert-butylN-(4-[(3-aminoquinolin-4-yl)amino]butyl)carbamate (149 g, 0.451 mol) wasreacted with triethyl orthoformate to provide crude product. Thismaterial was recrystallized from isopropyl alcohol to provide 84 g oftert-butyl N-[4-(1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate as acrystalline solid.

Part D

Using the general method of Example 1 Part D, tert-butylN-[4-(1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate (84.0 g, 0.247 mol)was oxidized to provide 87.9 g of1-[4-(tert-butylcarbamyl)butyl]-1H-imidazo[4,5-c]quinoline-5N-oxide as agreen/yellow foam.

Part E

Concentrated ammonium hydroxide (250 mL) was added to a vigorouslystirred solution of1-[4-(tert-butylcarbamyl)butyl]-1H-imidazo[4,5-c]quinoline-5N-oxide(87.9 g, 0.247 mol) in dichloromethane (750 mL). Tosyl chloride (47.0 g,0.247 mol) was added in small portions over a period of 30 minutes. Thereaction mixture was allowed to stir at ambient temperature overnightthen it was filtered to remove a tan precipitate. The filtrate layerswere separated. The aqueous layer was extracted with dichloromethane(4×50 mL). The dichloromethane fractions were combined, dried oversodium sulfate and then concentrated under vacuum to provide a pale tansolid. This material was recrystallized from isopropyl alcohol toprovide 75.7 g of tert-butylN-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate as a paleyellow solid, m.p. 171-173° C. ¹H NMR (500 MHz, CDCl₃) δ 8.19 (s, 1H),8.03 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H),7.26 (d, J=8.0 Hz, 1H), 6.83 (t, J=6.0 Hz, 1H), 6.60 (broad s, 2H), 4.59(t, J=7.0 Hz, 2H), 2.95 (q, J=6.0 Hz, 2H), 1.83 (quintet, J=7.0 Hz, 2H),1.42 (quintet, J=7.0 Hz, 2H), 1.33 (s, 9H). MS (EI) m/e 355.2001(355.2008 calcd for C₁₉H₂₅N₅O₂).

EXAMPLE 3 PhenylN-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate

A solution of 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (9.3mg, 36 μmol) in 10 mL of dichloromethane was cooled to −5° C. and asolution of phenyl chloroformate (7 mg, 45 μmol) in 1.5 mL ofdichloromethane was added, with argon bubbling to facilitate mixing. Themixture was then allowed to warm to room temp. while being vortexed for10 min. Aminomethylpolystyrene (ca. 80 mg, 1 meq/g, 100-200 mesh,Bachem) was added to quench excess chloroformate, and the mixture wasrefluxed and vortexed for several hours. The mixture was chromatographedthrough a short plug of silica gel with 10:1 dichloromethane-methanol aseluant to isolate the product as a solid. ¹H NMR (500 MHz, DMSO-d₆) δ8.28 (s, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.76 (t, J=5.6 Hz, 1H), 7.63 (d,J=8.2 Hz, 1H), 7.45 (t, J=7 Hz, 1H), 7.34 (t, J=8.2 Hz, 2H), 7.27 (t,J=7.5 Hz, 1H), 7.18 (t, J=7.3 Hz, 1H), 7.00 (d, J=8.6 Hz, 2H), 6.65 (bs,2H), 4.64 (t, J=7 Hz, 2H) 3.10 (q, J=6 Hz, 2H), 1.92 (quintet, J=7 Hz,2H), 1.52 (quintet, J=7 Hz, 2H). MS (APCI) m/e 376.15 (M+H).

EXAMPLE 4 9H-9-FluorenylmethylN-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate

To a solution of 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (9.3mg, 36 μmol) in 10 mL of dichloromethane at ambient temperature wasadded 9-fluorenylmethyl chloroformate (8 mg, 30 μmol) as a solid. Themixture was vortexed at room temperature for about 1 min., becomingslightly cloudy. Aminomethylpolystyrene (ca. 90 mg, 0.64 meq/g, 100-200mesh, Bachem) was added to quench excess chloroformate, and after a fewminutes the mixture was filtered through a short plug of silica gel,eluting with 10:1 dichloromethane-methanol to isolate the product as asolid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.27 (s, 1H), 8.08 (d, J=8.1 Hz, 1H),7.87 (d, J=7.6 Hz, 2H), 7.65 (m, 3H), 7.50 (t, J=7.6 Hz, 1H), 7.40 (t,J=7.3 Hz, 2H), 7.3 (m, 4H), 7.15 (bs, 2H), 4.62 (t, J=7 Hz, 2H), 4.27(d, J=7 Hz, 2H), 4.17 (t, J=7 Hz, 1H), 3.03 (q, J=7 Hz, 2H), 1.84(quintet, J=7 Hz, 2H), 1.45 (quintet, J=7 Hz, 2H). MS (APCI) m/e 478.28(M+H).

EXAMPLE 5N⁴-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-morpholinecarboxamide

4-Morpholinecarbonyl chloride (0.15 ml, 1.3 mmol) was added to astirring solution of 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine(0.3 g, 1.2 mmol) and pyridine (70 ml). The reaction was maintained atroom temperature overnight. The solvent was removed in vacuo and theresidue was purified by flash column chromatography (silica gel, 9:1dichloromethane\methanol). The fractions containing product werecombined, washed with saturated aqueous sodium bicarbonate, dried(MgSO₄), filtered, and concentrated to provide 0.86 g ofN⁴-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-morpholinecarboxamideas a tan powder, m.p. 177.0-179.5 ° C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.22(s, 1H), 8.04 (d, J=7.1 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.47 (t, J=7.1Hz, 1H), 7.28 (t, J=7.1 Hz, 1H), 6.72 (broad s, 2H), 6.52 (t, J=5.4 Hz,1H), 4.61 (t, J=6.9 Hz, 2H), 3.48 (t, J=4.6 Hz, 4H), 3.18 (t, J=4.6 Hz,4H), 3.05 (m, 2H), 1.84 (m, 2H), 1.44 (m, 2H); MS (EI) m/e 368.1966(368.1961 calcd for C₁₉H₂₄N₆O₂).

EXAMPLE 6N¹-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N-methyl-N-phenylurea

According to the general method of Example 5,1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine andN-methyl-N-phenylcarbamoyl chloride were combined to provideN¹-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N-methyl-N-phenylureaas a tan powder, m.p. 87.0-88.0° C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.19 (s,1H), 8.04 (d, J=8.1 Hz, 1H), 7.63 (dd, J=8.1, 1.2 Hz, 1H), 7.45 (dt,J=8.1, 1.2 Hz, 1H), 7.31-7.24 (m, 3H), 7.18-7.09 (m, 3H), 6.62 (s, 2H),5.95 (broad s, 1H), 4.59 (t, J=6.9 Hz, 2H), 3.07 (s, 3H), 3.03 (m, 2H),1.82 (quintet, J=7.2 Hz, 2H), 1.42 (quintet, J=7.2 Hz, 2H); MS (EI) m/e388.2023 (388.2012 calcd for C₂₂H₂₄N₆O).

EXAMPLE 7 (1R,2S,5R)-2-Isopropyl-5-methylcyclohexylN-[3-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate

(−)-Menthyl chloroformate (0.675 ml, 3.15 mmol) was added dropwise to astirring solution of 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine(0.80 g, 3.14 mmol) and pyridine (200 ml). The reaction was maintainedat room temperature overnight. The solvent was removed in vacuo and theresidue was purified by flash column chromatography (silica gel, 95:5dichloromethane\methanol). The fractions containing product werecombined, washed with saturated aqueous sodium bicarbonate, dried(MgSO₄), filtered, and concentrated to provide 0.32 g of(1R,2S,5R)-2-isopropyl-5-methylcyclohexylN-[3-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate as a tanpowder, m.p. 84.0-86.0° C. ¹³C NMR (75 MHz, DMSO-d₆) δ 156.5, 152.5,145.3, 143.1, 131.9, 128.5, 127.0, 126.5, 121.5, 120.8, 115.2, 73.0,47.2, 46.5, 41.7, 34.1, 31.2, 27.5, 26.8, 26.1, 23.4, 22.3, 20.8, 16.6;MS (EI) m/e 437.2797 (437.2791 calcd for C₂₅H₃₅N₅O₂).

EXAMPLE 8 2-NaphthylN-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate

According to the general method of Example 7,1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and chloroformic acid2-naphthyl ester were combined to provide 2-naphthylN-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate as a whitepowder, m.p. 154.0-155.0 ° C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.23 (s, 1H),8.08 (d, J=7.4 Hz, 1H), 7.94-7.86 (m, 4H), 7.64 (dd, J=8.3, 1.0 Hz, 1H),7.56-7.43 (m, 4H), 7.30 (m,1H), 7.20 (dd, J=8.8, 2.3 Hz, 1H), 6.61(broad s, 2H), 4.65 (t, J=6.9 Hz, 2H), 3.14 (q, J=6.4 Hz, 2H), 1.94 (m,2H), 1.56 (m, 2H); MS (EI) m/e 426.1927 (426.1930 calcd for C₂₅H₂₃N₅O₂).

EXAMPLE 9 1-NaphthylN-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate

According to the general method of Example 7,1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and chloroformic acid1-naphthyl ester were combined to provide 1-naphthylN-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate as a tanpowder, m.p. 89.0-92.0 ° C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.25 (s, 1H),8.10 (d, J=7.4 Hz, 1H), 8.05 (t, J=5.8 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H),7.79 (d, J=8.2 Hz, 1H), 7.66-7.45 (m, 6H), 7.30 (m, 1H), 7.19 (d, J=7.5Hz, 1H), 6.72 (broad s, 2H), 4.67 (t, J=6,9 Hz, 2H), 3.17 (q, J=6.3 Hz,2H), 1.96 (m, 2H), 1.59 (m, 2H); MS (EI) m/e 426.1929 (426.1930 calcdfor C₂₅H₂₃N₅O₂).

EXAMPLE 10N-{4-[4-Amino-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}urea

Part A

tert-ButylN-{4-[2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamatewas reacted according to the general method of Example 1 parts D and Eto provide tert-butylN-aminocarbonyl-N-{4-[4-amino-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamateas a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.93 (d, J=8.1 Hz, 1H), 7.86(broad s, 1H), 7.61 (dd, J=8.3, 1.1 Hz, 1H), 7.41 (m, 1H), 7.24-7.17 (m,4H), 6.87 (d, J=8.7 Hz, 2H), 6.55 (broad s, 2H), 4.45 (broad s, 2H),4.32 (s, 2H), 3.71 (s, 3H), 3.49 (m, 2H), 1.49 (m, 4H), 1.31 (s, 9H).

Part B

The tert-butyl carbamoyl group was removed from tert-butylN-aminocarbonyl-N-{4-[4-amino-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamateby heating the compound in a solution of HCI and ethanol. The reactionwas neutralized (NH₄OH) to provideN-{4-[4-amino-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}ureaas an off white solid, m.p. 196° C. (decomposition). ¹H NMR (300 MHz,DMSO-d₆) δ 7.96 (d, J=7.9 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.43 (t,J=7.6 Hz, 1H), 7.25 (m, 3H), 6.89 (d, J=8.6 Hz, 2H), 6.58 (broad s, 2H),5.92 (broad s, 1H), 5.36 (broad s, 2H), 4.41 (m, 2H), 4.32 (s, 2H), 3.72(s, 3H), 2.93 (d, J=5.8 Hz, 2H), 1.48 (m, 4H); MS (CI) m/e 419

EXAMPLE 11N⁴-{4-[4-Amino-2-(2-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-4-morpholinecarboxamide

According to the general method of Example5,1-(4-aminobutyl)-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-4-amineand 4-morpholinecarbonyl chloride were combined to provideN⁴-{4-[4-amino-2-(2-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-4-morpholinecarboxamide.¹H NMR (300 MHz, CDCI₃) δ 7.85-7.81 (m, 2H), 7.50 (m, 1H), 7.30 (m, 2H),7.17 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 5.62 (broad s, 2H), 4.36(m, 2H), 4.31 (s, 2H), 3.78 (s, 3H), 3.64 (t, J=4.9 Hz, 4H), 3.25 (t,J=4.9 Hz, 4H), 3.18 (m, 2H), 1.70 (m, 2H), 1.54 (m, 2H); MS (EI) m/e488.2533 (488.2536 calcd for C₂₇H₃₂N₆O₃).

EXAMPLE 12 tert-ButylN-[4-(4-Amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-1)butyl]carbamate

Part A

A solution of benzoyl chloride (5.3 g, 37.7 mmol) in dichloromethane(100 mL) was slowly added to a solution of tert-butylN-{4-[(3-aminoquinolin-4-yl)amino]butyl}carbamate (12.5 g, 37.7 mmol) indichloromethane (250 mL) at ambient temperature. The reaction mixturewas maintained at ambient temperature overnight. The resultingprecipitate was isolated by filtration and dried to provide 11.0 g oftert-butyl N-(4-{[3-(benzoylamino)quinolin-4-yl]amino}butyl)carbamatehydrochloride as a white solid.

Part B

Triethylamine (7.26 g, 71.7 mmol) was added to a solution of thematerial from Part A in ethanol (200 mL) and heated at reflux for 2days. The reaction mixture was concentrated to provide an orange syrup.HPLC mass spec analysis showed that the syrup contained the desiredproduct and starting material. The syrup was taken up in dichloromethane(100 mL) and then cooled in an ice bath. Triethylamine (5 mL) andbenzoyl chloride (1.9 mL) were added. The reaction mixture wasmaintained at ambient temperature for 2 days at which time analysis byHPLC indicated that the reaction was not complete. The reaction mixturewas concentrated under vacuum. The residue was taken up in isopropylalcohol (150 mL). Triethylamine (5 mL) was added and the reactionmixture was heated at reflux overnight. The reaction mixture wasconcentrated under vacuum. The residue was purified by flashchromatography (silica gel; eluting with 10% methanol indichloromethane). The fractions containing product were combined andconcentrated under vacuum. The residue was recrystallized fromacetonitrile to provide 6.7 g of tert-butylN-[4-(2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate as asolid, m.p. 158-159° C.

Part C

3-Chloroperoxybenzoic acid (1.05 eq of 65%) was slowly added in smallportions to a solution of tert-butylN-[4-(2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate (6.56 g,15.75 mmol) in dichloromethane (120 mL). After 3 hours the reaction wasquenched with 1% aqueous sodium bicarbonate (200 mL). The layers wereseparated. The aqueous layer was extracted with dichloromethane (2×50mL). The organic fractions were combined, dried over magnesium sulfateand then concentrated under vacuum to provide a pale orange syrup. Thesyrup was triturated with diethyl ether to provide 6.8 g of1-[4-(tert-butylcarbamyl)butyl]-2-phenyl-1H-imidazo[4,5-c]quinoline-5N-oxideas a pale tan solid, m.p. 178-181° C.

Part D

A solution of1-[4-(tert-butylcarbamyl)butyl]-2-phenyl-1H-imidazo[4,5-c]quinoline-5N-oxide(6.8 g, 15.75 mmol) in dichloromethane (100 mL) was chilled in an icebath. Concentrated ammonium hydroxide (30 mL) was added. Tosyl chloride(3.0 g, 15.75 mmol) was added in small portions over a period of 30minutes. The reaction mixture was allowed to warm to ambient temperatureovernight. The reaction was quenched with water (350 mL). The layerswere separated. The aqueous layer was extracted with dichloromethane.The organic fractions were combined, dried over magnesium sulfate andthen concentrated under vacuum to provide a tan solid. This material waspurified by flash chromatography (silica gel eluting with 10% methanolin dichloromethane) to provide 4.8 g of product. A small portion wasrecrystallized from toluene to provide tert-butylN-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate asa solid, m.p. 182-183° C. Analysis: Calculated for C₂₅H₂₉N₅O₂: %C,69.58; %H, 6.77; %N, 16.22; Found: %C, 69.86; %H, 6.95; %N, 15.80.

EXAMPLE 13N-[4-(4-Amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-propylthiourea

Part A

The tert-butyl N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin1-yl)butyl]carbamate (4.3 g, 10.0 mmol) was dissolved in methanol (15mL) and 1 N hydrochloric acid (100 mL) and then heated at reflux for 2hours. The reaction mixture was concentrated under vacuum to a volume ofabout 50 mL. Addition of concentrated ammonium hydroxide to pH 12 didnot produce a precipitate. The pH was adjusted to 7 with 1 Nhydrochloric acid. The mixture was extracted with dichloromethane andthen with ethyl acetate. The aqueous layer was concentrated to dryness.The residue was dissolved in water (50 mL) and then extractedcontinuously with refluxing chloroform for 36 hours. The chloroformextract was concentrated under vacuum to provide a light tan solid. Thismaterial was recrystallized from acetonitrile to provide 2.5 g of1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as an offwhite solid, m.p. 175-177° C. Analysis: Calculated for C₂₀H₂₁N₅: %C,72.48; %H, 6.39; %N, 21.13; Found: %C, 72.72; %H, 6.32; %N, 20.71.

Part B

A solution of propyl isothiocyanate (0.78 g, 7.72 mmol) in chloroform (5mL) was added at ambient temperature to a solution of1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine (0.256 g,7.72 mmol) in a mixture of chloroform (25 mL) and pyridine (5 mL). Thereaction mixture was maintained at ambient temperature over the weekend.The reaction was quenched with ethanol and then concentrated undervacuum to provide a pale orange syrup. This material was purified byflash chromatography (silica gel, eluting with 10% methanol indichloromethane). The pure fractions were combined and concentratedunder vacuum to provide 0.22 g ofN-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-propylthioureaas a white solid, m.p. 113-116° C. Mass spec M+1=433.2.

Example 14N-[4-(4-Amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-(3-pyridyl)thiourea

A solution of pyridine-3-isothiocyanate (0.136 g, 1.0 mmol) inchloroform (5 mL) was added at ambient temperature to a solution of1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine (0.331 g,1.0 mmol) in a mixture of chloroform (25 mL) and pyridine (5 mL). Thereaction mixture was maintained at ambient temperature over the weekend.The reaction was quenched with ethanol and then concentrated undervacuum to provide an off-white solid. This material was purified byflash chromatography (silica gel, eluting with 10% methanol indichloromethane). The pure fractions were combined and concentratedunder vacuum to provide 0.2 g ofN-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-(3-pyridyl)thioureaas a white solid, m.p. 118-120° C. Mass spec M+1=468.3. Analysis:Calculated for C₂₆H₂₅N₇S: %C, 66.79; %H, 5.39; %N, 20.97; Found: %C,64.29; %H, 5.46; %N, 20.06.

EXAMPLE 15N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-(4-fluorophenyl)urea

A solution of 4-fluorophenylisocyanate (0.137 g, 1.0 mmol) in chloroform(5 mL) was added at ambient temperature to a solution of1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine (0.331 g,1.0 mmol) in a mixture of chloroform (25 mL) and pyridine (5 mL). Thereaction mixture was maintained at ambient temperature over the weekend.The reaction was quenched with ethanol. The resulting pale yellowprecipitate (identified as the bis-adduct) was isolated by filtration.The filtrate was concentrated under vacuum to provide an off-whitesolid. This material was purified by flash chromatography (silica gel,eluting with 10% methanol in dichloromethane). The pure fractions werecombined and concentrated under vacuum to provide 0.22 g ofN-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-(4-fluorophenyl)ureaas a white solid, m.p. 145-150° C. Mass spec M+1=469.2. Analysis:C₂₇H₂₅FN₆O: %C, 69.21; %H, 5.37; %N, 17.94; Found: %C, 66.70; %H, 5.33;%N, 17.03.

EXAMPLES 16-52

The compounds shown in the table below were made according to thesynthetic method of Reaction Scheme II above.

A solution of 1-(4-aminobutyl)-]H-imidazo[4,5-c]quinolin-4-amine (36μmol) in 10 mL of dichloromethane in a screw-capped test tube was cooleddown to −5° C. The isocyanate (45 μmol) was added as a 0.3 M solution indichloromethane. Argon was bubbled through the mixture during additionand for an additional 15 seconds, and the mixture was allowed to standat −5° C. overnight. To this mixture was added approximately 90 mg of anaminomethyl polystyrene resin (0.62 meq/g, 100-200 mesh), and themixture was warmed to reflux and shaken at about 600 rpm for 3 hours.The mixtures were filtered through Poly-Prep columns (Bio-Rad #731-1550)to remove resin. Three different purification methods were used. InMethod A the filtrate was loaded onto a silica gel column. The columnwas eluted with 10:1 dichloromethane:methanol and the fractionscontaining product were combined and dried in vacuo. In Method C thefiltrates were dried in vacuo and purified by semi-preparative hplc on aGilson system (Rainin Microsorb C18 column, 21.4×250 mm, 8 micronparticle size, 60A pore, 10 mL/min., gradient elution from 2-95% B in 25min., hold at 95% B for 5 min., where A=0.1% trifluoroacetic acid/waterand B=0.1% Trifluoroacetic acid/acetonitrile, peak detection at 254 nmfor triggering fraction collection). The semi-prep hplc fractions wereanalyzed by LC-APCI/MS and the appropriate fractions were lyophilized toprovide the compounds as trifluoroacetate salts. In Method B thecompounds were purified by Method C and then the trifluoroacetate saltswere dissolved in ca. 3-5 mL of 2:1 dichloromethane-methanol and shakenwith ca. 80 mg (300 μmol) of diisopropylaminomethyl-polystyrene resin(Argonaut PS-DIEA, 3.86 mmol/g) for 1-2 h to liberate the free amine,and then filtered and dried in vacuo. The compounds were generallyamorphous solids.

Example APCI-MS No. Structure Purification m/e 500 MHz ¹H NMR 16

A 375.19 (DMSO-d₆) δ 8.38(s, 1H), 8.22(s, 1H), 8.05 (d, J=7.9Hz, 1H),7.61(d, 7.9Hz, 1H), 7.43 (t, J=7.6Hz, 1H), 7.36(d, J=7.3Hz, 2H), 7.24(t, J=7.3Hz, 1H), 7.20(t, J=7.9Hz, 2H), 6.87 (t, J=7.3Hz, 1H), 6.60(bs,2H), 6.14 (t, J=5.8Hz, 1H), 4.63(t, J=7Hz, 2H), 3.15 (q, J=6Hz, 2H),1.88(quintet, J=7Hz, 2H), 1.49 (quintet, J=7Hz, 2H) 17

B 420.16 (DMSO-d₆) δ 9.37(s, 1H), 8.42(s, 1H), 8.16 (d, J=7.8Hz, 1H),8.12(d, J=9.3Hz, 2H), 7.74 (d, J=8.3Hz, 1H), 7.59(m, 3H), 7.43(t, J=6Hz,1H), 6.58(t, J=5.4Hz, 1H), 4.68(t, J=7Hz, 2H), 3.15 (q, J=6Hz, 2H),1.89(quintet, J=7.5Hz, 2H), 1.52 (quintet, J=7Hz, 2H) 18

C 411.17 19

B 341.22 (DMSO-d₆) δ 8.40(s, 1H), 8.15(d, J=7.8Hz, 1H), 7.75(d, J=8.1Hz,1H), 7.62(t, J=7Hz, 1H), 7.46 (s, J=7Hz, 1H), 5.71(t, J=7Hz, 1H), 5.60(d, J=8Hz, 1H), 4.65(t, J=6.5Hz, 2H), 3.61 (sextet, J=7.5Hz, 1H),3.01(q, J=6Hz, 2H), 1.84 (quintet, J=7.5Hz, 2H), 1.42(quintet, J=7Hz,2H), 0.97(d, J=6.5Hz, 6H) 20

B 355.24 (DMSO-d₆) δ 8.42(s, 1H), 8.17(d, J=8.3Hz, 1H), 7.76(d, J=8.3Hz,1H), 7.64(t, J=8.5Hz, 1H), 7.48 (s, 1H), 5.66(t, J=6Hz, 1H), 5.54(s,1H), 4.66 (t, J=7Hz, 2H), 2.98(q, J=6Hz, 2H), 1.84 (quintet, J=8Hz, 2H),1.41(quintet, J=8Hz, 2H), 1.17 (s, 9H) 21

B 447.21 (DMSO-d₆) δ 8.43(s, 1H), 8.3(br s, 1H), 8.26 (s, 1H), 8.17(d,J=7.8Hz, 1H), 7.75 (d, J=8.3Hz, 1H), 7.61(t, J=8.1Hz, 1H), 7.44 (t,J=7.8Hz, 1H), 7.23(d, J=6.8Hz, 2H), 6.78 (d, J=6.8Hz, 2H), 6.12(t,J=6.1Hz, 1H), 4.68 (t, J=7Hz, 2H), 3.88(t, J=6.5Hz, 2H), 3.11 (q, J=6Hz,2H), 1.88(quintet, J=7Hz, 2H), 1.66 (quintet, # J=8Hz, 2H),1.49(quintet, J=7Hz, 2H), 1.41 (quintet, J=7Hz, 2H), 0.92(t, J=7Hz, 3H)22

B 447.00 (DMSO-d₆) δ 8.39(s, 1H), 8.28(bs, 1H), 8.15 (d, J=7.8Hz, 1H),7.75(d, J=7.8Hz, 1H), 7.61 (t, J=7.8Hz, 1H), 7.45(t, J=7.6Hz, 1H), 5.81(t, J=6Hz, 1H), 5.75(t, J=6Hz, 1H), 4.65 (t, J=7.5Hz, 2H), 3.02(q,J=6.5Hz, 2H), 2.92 (q, J=6.0Hz, 2H), 1.84(quintet, J=7.5Hz, 2H), 1.43(quintet, J=7Hz, 2H), 1.30(quintet, J=7Hz, 2H), # 1.22 (bs, J=8Hz, 8H),0.84(t, J=7.5Hz, 3H) 23

B 511.11 (DMSO-d₆) δ 9.6-8.6(b, 2H), 9.35(s, 1H), 8.55 (s, 1H), 8.24(d,J=8.0Hz, 1H), 8.06(s, 2H), 7.82 (d, J=8.0Hz, 1H), 7.69(t, J=8.0Hz, 1H),7.55(t, J= 8.0Hz, 1H), 7.54(s, 1H), 6.70(t, J=6.0, 1H), 4.72 (t,J=7.5Hz, 2H), 3.15(q, J=6.0Hz, 2H), 1.90 (quintet, J=7.0Hz, 2H),1.54(quintet, J=7.5Hz, 2H) 24

B 459.35 (DMSO-d₆) δ 8.32(bs, 1H), 8.28(bs, 1H), 8.13 (d, J=8.8Hz, 1H),7.70(d, J=7.6Hz, 1H), 7.55 (t, J=6.8Hz, 1H), 7.38(t, 1H), 7.34(bs, 1H),7.17 (t, J=8Hz, 1H), 7.06(d, J=8Hz, 2H), 6.1(bs, 2H), 4.66(t, J=7.5Hz,2H), 3.10(bs, 2H), 3.04 (quintet, J=7Hz, 1H), 1.88(bm, 2H), 1.48(bm,2H), 1.02(d, J=7Hz, 12H) 25

C 383.22 (DMSO-d₆) δ 8.52(s, 1H), 8.22(d, J=8Hz, 1H), 7.83(d, J=8Hz,1H), 7.72(t, J=8Hz, 1H), 7.58 (t, J=8Hz, 1H), 5.80(t, J=5Hz, 1H), 5.75(t, J=5.5Hz, 1H), 4.68(t, J=7.0Hz, 2H), 3.02 (q, J=6.5Hz, 2H), 2.92(q,J=6Hz, 2H), 1.84 (quintet, J=7Hz, 2H), 1.44(quintet, J=7Hz, 2H), 1.29(t, J=7Hz, 2H), 1.2(m, 6H), 0.84(t, J=7Hz, 3H) 26

C 341.21 (DMSO-d₆) δ 8.52(s, 1H), 8.23(d, J=8Hz, 1H), 7.83(d, J=8Hz,1H), 7.72(t, J=7.5Hz, 1H), 7.57 (t, J=7Hz, 1H), 5.80(t, J=6.5Hz, 1H),5.77 (t, J=6Hz, 1H), 4.68(t, J=7.5Hz, 2H), 3.02 (q, J=6.5Hz, 2H),2.89(q, J=6.5Hz, 2H), 1.84 (quintet, J=7.5Hz, 2H), 1.43(quintet, J=8Hz,2H), 1.31(sextet, J=7Hz, 2H), 0.78(t, J=7.5Hz, 3H) 27

C 417.18 (DMSO-d₆) δ 9.6-8.6(b, 2H), 8.55(s, 1H), 8.33 (bs, 1H), 8.24(d,J=7.5Hz, 1H), 7.83 (d, J=7.5Hz, 1H), 7.72(t, J=7.5Hz, 1H), 7.56 (t,J=7.5Hz, 1H), 7.25(d, J=8.0Hz, 2H), 7.06(d, J=8 Hz, 2H), 6.17(t,J=5.5Hz, 1H), 4.71(t, J=7.0 Hz, 2H), 3.12(q, J=5.5Hz, 2H), 2.79(quintet,J= 7.0Hz, 1H), 1.89(quintet, J=7.0Hz, 2H), # 1.51 (quintet, J=7.0Hz,2H), 1.16(d, J=7.0Hz, 6H) 28

B 400.18 (DMSO-d₆) δ 8.88(s, 1H), 8.32(s, 1H), 8.22 (bs, 1H), 8.11(d,J=8Hz, 1H), 7.91(t, J=1.7Hz, 1H), 7.68(d, J=8Hz, 1H), 7.55(d, J=9.5Hz,1H), 7.51 (t, J=8.1Hz, 1H), 7.41(t, J=8.3Hz, 1H), 7.34 (t, J=7.1Hz, 1H),6.41(t, J=7Hz, 1H), 4.66 (t, J=6.5Hz, 2H), 3.13(q, J=6Hz, 2H), 1.89(quintet, J=7.5Hz, 2H), 1.50(quintet, J=7Hz, 2H) 29

B 443.10 (DMSO-d₆) δ 8.97(s, 1H), 8.46(s, 1H), 8.19 (d, J=7.8Hz, 1H),7.77(d, J=8.3Hz, 1H), 7.63 (t, J=8.1Hz, 1H), 7.48(t, J=7.3Hz, 1H),7.44(s, 2H), 7.05(t, J=1.7Hz, 1H), 6.49(t, J=5.6Hz, 1H), 4.69 (t, J=7Hz,2H), 3.12(q, J=6.5Hz, 2H), 1.88 (quintet, J=8Hz, 2H), 1.50(quintet,J=7Hz, 2H) 30

B 369.24 (DMSO-d₆) δ 8.80(b, 2H), 8.52(s, 1H), 8.23(d, J=7.5Hz, 1H),7.84(d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.58(t J=7.5Hz, 1H),5.80(t, J=5.5Hz, 1H), 5.75(t, J=5.5Hz, 1H), 4.68(t, J= 7.0Hz, 2H),3.02(q, J=5.5Hz, 2H), 2.92(q, J=5.5Hz, 2H), 1.84(quintet, J=7.0Hz, 2H),1.44 (quintet, J=7.0Hz, 2H), 1.30(quintet, J= 7.0Hz, # 2H),1.23(quintet, J=7.0Hz, 2H), 1.18 (sextet, J=7.0Hz, 2H), 0.83(t, J=7.0Hz,3H) 31

B 477.08 (DMSO-d₆) δ 9.6-8.6(b, 2H), 8.60(d, J=2.0Hz, 1H), 8.56(s, 1H),8.26(s, 1H), 8.25(d, J=8Hz, 1H), 7.82(d, J=8.0Hz, 1H), 7.69(t, j=8.0Hz,1H), 7.64(d, J=8.0Hz, 1H), 7.55(t, J=8.0Hz, 1H), 7.28(dd, J=8.0, 2.0Hz,1H), 7.23(t, J=5.5 Hz, 1H), 4.72(t, J=7.0Hz, 2H), 3.16(q, J=5.5 Hz, 2H),1.92(quintet, J=7Hz, 2H), # 1.54(quintet, J=7.0Hz, 2H) 32

B 411.23 (DMSO-d₆) δ 9.6-8.6(b, 2H), 8.53(s, 1H), 8.24 (d, J=8.5Hz, 1H),7.84(d, J=8.5Hz, 1H), 7.74 (t, J=8.5Hz, 1H), 7.59(t, J=8.5Hz, 1H), 5.63(t, J=6.0Hz, 1H), 5.44(s, 1H), 4.70(t, J=7.0Hz, 2H), 2.98(q, J=6.0Hz,2H), 1.83(quintet, J=7.0Hz, 2H), 1.59(s, 2H), 1.40(quintet, J=7.0Hz,2H), 1.19 (s, 6H), 0.84(s, 9H) 33

C 467.21 34

C 431.26 35

C 389.20 36

C 403.22 37

C 405.19 38

C 417.24 39

C 381.26 40

C 403.23 41

C 420.18 42

C 453.09 43

C 433.18 44

C 419.18 45

C 451.17 46

C 443.14 47

C 421.14 48

C 389.18 49

C 421.14 50

C 475.20 51

C 417.20 52

C 355.21

EXAMPLES 53-66

The examples in the table below were prepared according to the syntheticmethod of Reaction Scheme II above using the following general method.1-(2-Aminoethyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (50 mg),dichloromethane (2 mL) and the isocyanate were placed in a 2 dram (7.4mL) vial. The vial was placed on a shaker for about 2-16 hours atambient temperature. The reaction mixture was analyzed by LC/MS toconfirm the formation of the desired product. The solvent was removedand the residue was purified by semi-preparative HPLC (Capcell Pak C18column, 35 mm×20 mm, 5 micron particle size, 20 mL/min., gradientelution from 5-95% B in 10 min., hold at 95% B for 2 min., where A=0.1%trifluoroacetic acid/water and B=0.1% trifluoroacetic acid/acetonitrile,peak detection at 254 nm for triggering fraction collection). Thesemi-prep HPLC fractions were analyzed by LC-APCI/MS and the appropriatefractions were combined and lyophilized to provide the trifluoroacetatesalt of the desired urea.

Example # Structure of the Free Base mass 53

461.2 54

495.1 55

417.1 56

369.2 57

355 58

369.2 59

383.3 60

403.2 61

417.2 62

417.2 63

417.2 64

428.2 65

431.2 66

431.2

EXAMPLES 67-69

The examples in the table below were prepared using the followingmethod.1-(2-Aminoethyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-aminehydrochloride (50 mg), dichloromethane (2 mL) and diisopropylethylamine(1.2 eq) were placed in a 2 dram (7.4 mL) vial. The vial was placed on ashaker for about 1 hour at ambient temperature. The appropriate(thio)isocyanate was added and the vial was shaken at ambienttemperature for about 4 hours. The reaction mixture was analyzed byLC/MS to confirm the formation of the desired product. The solvent wasremoved and the residue was purified by semi-preparative HPLC (CapcellPak C18 column, 35 mm×20 mm, 5 micron particle size, 20 mL/min.,gradient elution from 5-95% B in 10 min., hold at 95% B for 2 min.,where A=0.1% trifluoroacetic acid/water and B=0.1% trifluoroaceticacid/acetonitrile, peak detection at 254 nm for triggering fractioncollection). The semi-prep HPLC fractions were analyzed by LC-APCI/MSand the appropriate fractions were combined and lyophilized to providethe trifluoroacetate salt of the desired (thio)urea.

Example # Structure of the Free Base Mass 67

371.1 68

405.1 69

427.1

EXAMPLES 70-99

The examples in the table below were prepare according to the syntheticmethod of Reaction Scheme II above by reacting1-(4-aminobutyl)-2-butyl-1Himidazo[4,5-c]quinolin-4-amine with theappropriate isocyanate using the general method of Examples 53-66 above.

Example # Structure of Free Base Mass 70

395.2 71

397.3 72

411.3 73

431.2 74

437.3 75

445.2 76

445.20 77

445.2 78

449.2 79

449.2 80

456.2 81

459.3 82

459.3 83

459.3 84

459.3 85

461.3 86

465.2 87

467.3 88

471.3 89

475.3 90

476.2 91

476.2 92

479.2 93

499.2 94

499.2 95

499.2, 501.1 96

499.2, 501.1 97

509, 511.1 98

509, 511.1 99

509, 511.1

EXAMPLES 100-119

The examples in the table below were prepare according to the syntheticmethod of Reaction Scheme II above by reacting1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-aminewith the appropriate isocyanate using the general method of Examples53-66 above.

Example # Structure of the Free Base Mass 100

491.3 101

385.2 102

399.2 103

413.2 104

433.2 105

439.2 106

447.2 107

451.1 108

458.2 109

458.2 110

461.2 111

461.2 112

467.1 113

467.1 114

478.1 115

478.1 116

501.2 117

501.2 118

501.0, 503.1 119

511, 513.1

EXAMPLES 120-122

The examples in the table below were prepared according to the syntheticmethod of Reaction Scheme III above using the following method.1-(4-Aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(50 mg), diisopropylethylamine (34 μL), dichloromethane (2 mL) and thecarbamyl chloride (1.1 eq) were placed in a 2 dram (7.4 mL) vial. Thevial was placed on a shaker for about 2 hours at ambient temperature.The reaction mixture was analyzed by LC/MS to confirm the formation ofthe desired product. The solvent was removed and the residue waspurified by semi-preparative HPLC (Capcell Pak C18 column, 35 mm×20 mm,5 micron particle size, 20 mL/min., gradient elution from 5-95% B in 10min., hold at 95% B for 2 min., where A=0.1% trifluoroacetic acid/waterand B=0.1% trifluoroacetic acid/acetonitrile, peak detection at 254 nmfor triggering fraction collection). The semi-prep HPLC fractions wereanalyzed by LC-APCI/MS and the appropriate fractions were combined andlyophilized to provide the trifluoroacetate salt of the desired urea.

Example # Structure of the Free Base Mass 120

447.3 121

427.2 122

411.3

EXAMPLES 123-124

The examples in the table below were prepare according to the syntheticmethod of Reaction Scheme II above by reacting1-(4-aminobutyl)-2-(4-methoxyphenylmethyl)-1H-imidazo[4,5-c]quinolin-4-aminewith the appropriate isocyanate using the general method of Examples53-66 above.

Example # Structure of the Free Base Mass 123

461.3 124

495.3

EXAMPLES 125-131

The examples in the table below were prepared according to the syntheticmethod of Reaction Scheme II above using the following method.1-(4-Aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(50 mg), dichloromethane (2 mL) and the thioisocyanate (1.1 eq) wereplaced in a 2 dram (7.4 mL) vial. The vial was placed on a sonicator forabout 30-60 minutes at ambient temperature. The reaction mixture wasanalyzed by LC/MS to confirm the formation of the desired product. Thesolvent was removed and the residue was purified by semi-preparativeHPLC (Capcell Pak C18 column, 35 mm×20 mm, 5 micron particle size, 20mL/min., gradient elution from 5-95% B in 10 min., hold at 95% B for 2min., where A=0.1% trifluoroacetic acid/water and B=0.1% trifluoroaceticacid/acetonitrile, peak detection at 254 nm for triggering fractioncollection). The semi-prep HPLC fractions were analyzed by LC-APCI/MSand the appropriate fractions were combined and lyophilized to providethe trifluoroacetate salt of the desired thiourea.

Example # Structure of the Free Base Mass 125

450.1 126

542.2 127

415.1 128

449.1 129

413.1 130

429.2 131

499.2

EXAMPLES 132-137

The examples in the table below were prepared according to the syntheticroute shown in Reaction Scheme VII above.

Part A

The tetrahydroquinoline amine starting materials were prepared asfollows.

A catalytic amount of platinum (IV) oxide was added to a solution of1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (2.2 g, 7.06mmol) in trifluoroacetic acid (200 mL). The reaction mixture washydrogenated at 50 psi (3.44×10⁵ Pa) on a Parr apparatus for 6 days. Thereaction mixture was filtered to remove the catalyst and the filtratewas concentrated under vacuum. The residue was combined with 1 Nhydrochloric acid (100 mL) and heated on a steam bath for 2 hours. Themixture was cooled, made basic with ammonium hydroxide and thenextracted with dichloromethane. The extract was concentrated undervacuum to provide of 1-(4-aminobutyl)-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as a solid, m.p.63-67° C.

A catalytic amount of platinum (IV) oxide was added to a solution of1-(4-aminobutyl)-2-methoxyethyl-1H-imidazo[4,5-c]quinolin-4-amine (7.7g, 24.5 mmol) in trifluoroacetic acid (250 mL). The reaction mixture washydrogenated at 50 psi (3.44×10⁵ Pa) on a Parr apparatus. The progressof the reaction was monitored by LC/MS. Additional catalyst was added 7,11, and 17 days after the start of the reaction. After 25 days thereaction was complete. The reaction mixture was filtered through a layerof Celite® filter aid to remove the catalyst and the filtrate wasconcentrated under vacuum. The residue was combined with 1 Nhydrochloric acid (100 mL) and stirred overnight. The mixture was madebasic (pH=11) with ammonium hydroxide and then extracted withdichloromethane (3×300 mL). The extracts were combined and concentratedunder vacuum to provide 3.5 g of1-(4-aminobutyl)-6,7,8,9-tetrahydro-2-methoxyethyl-1H-imidazo[4,5-c]quinolin-4-amineas a solid.

Part B

The tetrahydroimidazoquinoline amines from Part A were reacted with theappropriate isocyanate or sulfonyl isocyanate using the general methodof Examples 53-66 above to provide the trifluoroacetate salt of thedesired urea or sulfonyl urea.

Example # Structure of the Free Base Mass 132

493.20 133

449.2  134

389.2  135

431.2  136

437.2  137

499.1 

EXAMPLES 138-140

The examples in the table below were prepared according to the syntheticmethod of Reaction Scheme VI above using the following procedure. The1H-imidazo[4,5-c]quinolin-4-amine (50 mg), dichloromethane (2 mL) andthe sulfonylisocyanate (1.3 eq) were placed in a 2 dram (7.4 mL) vial.The vial was placed on a shaker at ambient temperature. The reactionmixture was analyzed by LC/MS to confirm the formation of the desiredproduct. The solvent was removed and the residue was purified bysemi-preparative HPLC (Capcell Pak C18 column, 35 mm×20 mm, 5 micronparticle size, 20 mL/min., gradient elution from 5-95% B in 10 min.,hold at 95% B for 2 min., where A=0.1% trifluoroacetic acid/water andB=0.1% trifluoroacetic acid/acetonitrile, peak detection at 254 nm fortriggering fraction collection). The semi-prep HPLC fractions wereanalyzed by LC-APCI/MS and the appropriate fractions were combined andlyophilized to provide the trifluoroacetate salt of the desiredsulfonylurea.

Example # Structure of the Free Base Mass 138

495.2 139

485.0 140

501.0, 503.0

EXAMPLE 141N¹-{4-[4-Amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl)-N³-benzoylureaTrifluoroacetate

This compound was prepared according to the synthetic method of ReactionScheme V above. The1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(50 mg), dichloromethane (2 mL) and benzoylisocyanate (1.1 eq) wereplaced in a 2 dram (7.4 mL) vial. The vial was placed on a shaker for 2hours at ambient temperature. The reaction mixture was analyzed by LC/MSto confirm the formation of the desired product. The solvent was removedand the residue was purified by semi-preparative HPLC (Capcell Pak C18column, 35 mm×20 mm, 5 micron particle size, 20 mL/min., gradientelution from 5-95% B in 10 min., hold at 95% B for 2 min., where A=0.1%trifluoroacetic acid/water and B=0.1% trifluoroacetic acid/acetonitrile,peak detection at 254 nm for triggering fraction collection). Thesemi-prep HPLC fractions; were analyzed by LC-APCI/MS and theappropriate fractions were combined and lyophilized to provide thetrifluoroacetate salt of the desired compound. MS (APCI) m/e 461.2(M+H).

EXAMPLE 142N-{4-[4-Amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamateTrifluoroacetate

This compound was prepared according to the synthetic method of ReactionScheme IV above. The1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(50 mg), diisopropylethylamine (1.2 eq.), dichloromethane (2 mL) andbenzyl chloroformate (1.1 eq) were placed in a 2 dram (7.4 mL) vial. Thevial was placed on a shaker for 2 hours at ambient temperature. Thereaction mixture was analyzed by LC/MS to confirm the formation of thedesired product. The solvent was removed and the residue was purified bysemi-preparative HPLC (Capcell Pak C18 column, 35 mm×20 mm, 5 micronparticle size, 20 mL/min., gradient elution from 5-95% B in 10 min.,hold at 95% B for 2 min., where A=0.1% trifluoroacetic acid/water andB=0.1% trifluoroacetic acid/acetonitrile, peak detection at 254 nm fortriggering fraction collection). The semi-prep HPLC fractions wereanalyzed by LC-APCI/MS and the appropriate fractions were combined andlyophilized to provide the trifluoroacetate salt of the desiredcompound. MS (APCI) m/e 448.2 (M+H).

EXAMPLE 143N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea

Triethylamine (0.59 mL, 4.3 mmol) was added to a solution of1-(4-aminobutyl)-2ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.5mmol) in chloroform (100 mL). The solution was stirred in an ice bathfor 5 min. Phenyl isocyanate (0.38 mL, 3.5 mmol) was slowly added. Theresulting precipitate was isolated by filtration, washed with chloroform(4×30 mL), and then dried in an Abderhalden drying apparatus overnightto provide 1.11 g ofN-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylureaas a white solid, m.p. 179.7-181.4° C. Analysis: Calculated forC₂₃H₂₆N₆O. 0.6H₂O: %C, 66.84; %H, 6.63; %N, 20.33; Found: %C, 67.20; %H,6.61; %N, 20.46.

EXAMPLE 144N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea

Using the general method of Example 143,1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (500 mg, 1.9mmol) was reacted with phenyl isocyanate to provide 123 mg ofN-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylureaas a light brown solid, m.p. 171.5-172.5° C. Analysis: Calculated forC₂₂H₂₄N₆O.0.60 H₂O: %C 66.18; %H, 6.36; %N, 21.05; Found: %C, 66.05; %H,6.43; %N, 20.61.

EXAMPLE 145N-(8-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]octyl}-N′-phenylurea

Under a nitrogen atmosphere a mixture of1-(8-aminooctyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(1.5 g, 4.06 mmol) and dichloromethane (50 mL) was cooled to 0° C.Phenyl isocyanate was added dropwise. The reaction mixture was allowedto slowly warm to ambient temperature overnight. The reaction mixturewas concentrated under reduced pressure. The crude product was purifiedby column chromatography (110 g silica gel eluting with 9:1dichloromethane:methanol). The resulting orange solid was trituratedwith hexanes, isolated by filtration and then dried. This material wasrecrystallized from propyl acetate with a small amount of methanol,isolated by filtration, washed with hexanes, and then dried in a vacuumoven at 60° C. for 2 days to provide 0.6 g ofN-{8-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]octyl}-N′-phenylureaas an off white powder, m.p. 136-142° C. Analysis: Calculated forC₂₈H₃₆N₆O₂: %C, 68.83; %H, 7.43; %N, 17.20; Found: %C, 68.27; %H, 7.44;%N, 16.85. ¹H NMR (300 MHz, DMSO-d₆) δ 8.36 (s, 1H), 8.01 (d, J=7.8 Hz,1H), 7.61 (dd, J=8.3-1.0 Hz, 1H), 7.44-7.35 (m, 3H), 7.29-7.17 (m, 3H),6.87 (t, J=7.3 Hz, 1H), 6.52 (s, 2H), 6.08 (m, 1H), 4.51 (t, J=7.8 Hz,2H), 3.82 (m, 2H), 3.29 (s, 3H), 3.18 (t, J=6.8 Hz, 2H), 3.05 (m, 2H),1.81 (m, 2H), 1.42-1.29 (m, 10H); ¹³C NMR (75 MHz, DMSO-d₆) 155.5,152.0, 151.0, 145.0, 141.0, 132.6, 128.9, 126.8, 126.7, 126.6, 121.5,121.2, 120.7, 117.9, 115.1, 70.5, 58.5, 45.3, 30.1, 29.0, 27.5, 26.6,26.2. MS m/z 489 (M+H).

EXAMPLE 146N-[3-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-phenylurea

Part A

tert-butyl 3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate(˜-80 g) was dissolved in 1,4-dioxane (400 mL) with gentle heating.Hydrochloric acid (55 mL of 4.0 M in 1,4-dioxane) was added in a singleportion and the reaction was heated to reflux. The reaction wasmonitored by HPLC. Additional acid (150-200 mL) was added and thereaction mixture was refluxed until the reaction was complete. Thereaction mixture was cooled to ambient temperature. A solid was isolatedby filtration to give ˜72 g of3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamine hydrochloride.This material was combined with that from a previous experiment and thendissolved in water (400 mL). The solution was neutralized with solidpotassium carbonate. At pH 7 a solid precipitated. The solid wasisolated by filtration and then dissolved in water (1500 mL). The pH wasadjusted to pH 10 with solid potassium carbonate. The solution wasextracted with chloroform until HPLC analysis showed that no amineremained in the aqueous layer. The organic layers were combined and thenconcentrated under reduced pressure to provide 45 g of3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamine.

Part B

A solution of phenyl isocyanate (1.00 g, 7.79 mmol) in dichloromethane(10 mL) was added dropwise over 5 minutes with stirring to a solution of3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamine (2.00 g, 7.08mmol) in dichloromethane (50 mL). The resulting precipitate was isolatedby filtration to provide 2.50 g ofN-[3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-phenylurea.

Part C

3-Chloroperoxybenzoic acid (1.72 g of ˜60%) was added in small portionsover a period of 15 minutes to a suspension of the material from Part Bin chloroform (75 mL). A solution was obtained during the addition. Thereaction mixture was allowed to stir overnight and then it was filteredto provide 1.2 g ofN-[3-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-phenylureaas a light blue solid. The filtrate was combined with 1% aqueous sodiumbicarbonate (100 mL). The layers were separated. The aqueous layer wasextracted with chloroform (3×70 mL) and then filtered to provide 1.05 gofN-[3-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-phenylureaas an off white solid.

Part D

Concentrated ammonium hydroxide (35 mL) was added with stirring to asolution ofN-[3-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-phenylurea(2.25 g, 5.39 mmol) in dichloromethane (100 mL). Tosyl chloride (1.13 g,5.93 mmol) was added in small portions over a period of 30 minutes.After I hour the layers were separated. The aqueous layer was extractedwith dichloromethane (2×25 mL). The organics were combined and extractedwith water (3×50 mL). The aqueous layers were combined and filtered toprovide 1.64 g of an off white solid. This material was recrystallizedsequentially from 1,2-dichloroethane, isopropyl alcohol and methanol toprovide 960 mg ofN-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-phenylureaas light tan needles, m.p. 191-192° C. Analysis: Calculated forC₂₄H₂₈N₆O: %C, 69.21; %H, 6.78; %N, 20.18; Found: %C, 68.94; %H, 6.77;%N, 19.90.

EXAMPLE 147 tert-Butyl3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate

Part A

Using the general method of Example 146 Part C, tert-butyl3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate (27.0 g) wasoxidized to provide 39 g of tert-butyl3-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate as alight gray solid.

Part B

Using the general method of Example 146 Part D, tert-butyl3-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate (28.13g) was aminated to provide 26.75 g of crude product. A small portion wasrecrystallized from toluene and then further purified by columnchromatography (silica gel eluting with 5% methanol in dichloromethane).The purified material was recrystallized from acetonitrile to provide0.15 g of tert-butyl3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate aswhite solid, m.p. 192.7-193.4° C. Analysis: Calculated for C₂₂H₃₁N₅O₂:%C, 66.47; %H, 7.86; %N, 17.62; Found: %C, 66.49; %H, 7.94; %N, 17.76.

EXAMPLE 148 tert-Butyl3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate

Part A

Using the general method of Example 146 Part C, tert-butyl3-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate(˜80 g) was oxidized to provide tert-butyl3-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate.

Part B

Using the general method of Example 146 Part D, the material from Part Awas aminated to provide crude product. A small portion wasrecrystallized from acetonitrile to provide 1.27 g of tert-butyl3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamateas a solid, m.p. 174.2-175.8° C. Analysis: Calculated for C₂₁H₂₉N₅O₃:%C, 63.14; %H, 7.32; %N, 17.53; Found: %C, 62.89; %H, 7.23; %N, 17.42.

EXAMPLE 149N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-phenylthiourea

Phenyl isothiocyanate (750 mg, 5.55 mmol) was added dropwise withstirring to a chilled (0° C.) solution of1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.36mmol) in 1-methyl-2-pyrrolidinone (50 mL). The reaction mixture waspoured into water (500 mL) and the pH adjusted to 10 with solidpotassium carbonate. The resulting precipitate was isolated byfiltration and then rinsed with water. This material was slurried withhot methanol and then purified by column chromatography (silica geleluting with 2% methanol in dichloromethane to 7% methanol indichloromethane). The purified material was recrystallized fromisopropanol to provide 950 mg ofN-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-phenylthioureaas a white solid, m.p. 142.8-144.0° C. Analysis: Calculated forC₂₄H₂₈N₆S. C₃H₈O: %C, 65.82; %H, 7.37; %N, 17.06; Found: %C, 65.77; %H,7.41; %N, 17.11.

EXAMPLE 150N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-butylurea

Triethylamine (765 mg, 7.56 mmol) was added to a solution of1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 5.04mmol) in 1-methyl-2-pyrrolidinone (100 mL). Butyl isocyanate (549 mg,5.55 mmol) was added dropwise with stirring. The reaction mixture wasallowed to stir overnight and then it was poured into water (500 mL).The pH was adjusted to 10 using solid potassium carbonate. The resultingprecipitate was isolated by filtration, washed with water and thenpurified by column chromatography (silica gel eluting with 5% methanolin dichloromethane and then with 10% methanol in dichloromethane. Thepurified material was recrystallized from acetonitrile to provide 800 mgofN-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-butylureaas a white solid, m.p. 185.5-186.4° C. Analysis: Calculated forC₂₂H₃₂N₆O: %C, 66.64; %H, 8.13; %N, 21.29; Found: %C, 66.38; %H, 8.19;%N, 21.10.

EXAMPLE 151N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]morpholine-4-carboxamide

Using the general method of Example 149,1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.36mmol) was reacted with 4-morpholinecarbonyl chloride (830 mg, 5.55 mmol)to provide 650 mg ofN-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]morpholine-4-carboxamideas a white powder, m.p. 193.4-194.6° C. Analysis: Calculated forC₂₂H₃₀N₆O₂: %C, 64.37; %H, 7.37; %N, 20.47; Found: %C, 64.00; %H, 7.32;%N, 20.16.

EXAMPLE 152N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-propylthiourea

Using the general method of Example 150,1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 5.04mmol) was reacted with propyl isothiocyanate (560 mg, 5.55 mmol) toprovide 1.34 g ofN-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-propylthioureaas a crystalline solid, m.p. 144.5-145.5° C. Analysis: Calculated forC₂₁H₃₀N₆S. 0.56 H₂O: %C, 61.72; %H, 7.68; %N, 20.56; Found: %C, 61.72;%H, 7.67; %N, 20.56.

EXAMPLE 153N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-cyclohexylurea

Part A

Using the general method of Example 146 Part B,3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamine (2.00 g, 7.08mmol) was reacted with cyclohexyl isocyanate (1.0 g, 7.98 mmol) toprovide 2.62 g ofN-[3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-cyclohexylurea.

Part B

Using the general method of Example 146 Part C, the material from Part Awas oxidized to provide 2.37 g ofN-[3-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-cyclohexylureaas an off white solid.

Part C

Using the general method of Example 146 Part D, the material from Part Bwas aminated to provide 380 mg ofN-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-cyclohexylureaas a white powder, m.p. 200-201° C. Analysis: Calculated forC₂₄H₃₄N₆O.1.19 H₂O: %C, 64.92; %H, 8.26; %N, 18.93; Found: %C, 65.09;%H, 8.39; %N, 18.85.

EXAMPLE 154N-[8-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)octyl]-N′-phenylurea

Using the general method of Example 145,1-(8-aminooctyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.2 g, 3.26mmol) was reacted with phenyl isocyanate to provide 1.59 g ofN-[8-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)octyl]-N′-phenylureaas an off white powder, m.p. 153-155° C. Analysis: Calculated forC₂₉H₃₈N₆O.0.20 H₂O: %C, 71.05; %H, 7.89; %N, 17.14; Found: %C, 70.86;%H, 7.97; %N, 16.87. ¹H NMR (300 MHz, DMSO-d₆) δ 8.34 (s, 1H), 8.01 (d,J=7.8 Hz, 1H), 7.61 (dd, J=8.3, 1.0 Hz, 1H), 7.43-7.36 (m, 3H),7.26-7.17 (m, 3H), 6.87 (t, J=7.3 Hz, 1H), 6.49 (s, 2H), 6.08 (m, 1H),4.49 (m, 2H), 3.05 (m, 2H), 2.91 (m, 2H), 1.80 (m, 4H), 1.43-1.29 (m,12H), 0.95 (t, J=7.3 Hz, 3H); ¹³C NMR (125 MHz, DMSO-d₆) 155.5, 153.4,152.0, 144.9, 141.0, 132.6, 128.9, 126.7, 126.62, 126.57, 121.5, 121.2,120.2, 117.9, 115.1, 45.1, 39.3, 30.1, 30.0, 29.0, 28.9, 26.6, 26.5,26.2, 22.3, 14.1; MS m/z 487 (M+1)

EXAMPLE 155N-[4-(4-amino-2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea

Part A

Using the general method of Example 146 Part A, tert-butyl4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butylcarbamate (5.0 g, 11.8mmol)was hydrolyzed to provide 1.27 g4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butylamine as an off-whitecrystalline solid, m.p. 171.0-172.4° C.

Part B

Using the general method of Example 146 Part B,4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butylamine (4.0 g, 12.3 mmol)was reacted with phenyl isocyanate (1.34 mL, 12.3 mmol) to provide 4.77g of N-[4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea.

Part C

Using the general method of Example 146 Part C, the material from Part Bwas oxidized to provideN-[4-(2-hexyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N1-phenylurea.

Part D

Using the general method of Example 146 Part D, the material from Part Cwas aminated to provide 2.20 g ofN-[4-(4-amino-2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylureaas a light brown solid, m.p. 170.4-171.6° C. Analysis: Calculated forC₂₇H₃₄N₆O.0.50 H₂O: %C, 69.35; %H, 7.54; %N, 17.97; Found: %C, 69.02;%H, 7.42; %N, 17.80.

EXAMPLE 156N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-N′-propylthiourea

Using the general method of Example 149,1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(1.53 g, 5.11 mmol) was reacted with propyl isothiocyanate (570 mg, 5.62mmol) to provide 950 mg ofN-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}N′-propylthioureaas a tan powder, m.p. 172-173° C. Analysis: Calculated for C₂₀H₂₈N₆OS:%C, 59.97; %H, 7.05; %N, 20.98; Found: %C, 59.83; %H, 7.01; %N, 20.95.

EXAMPLE 157N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-N′-cyclohexylthiourea

Using the general method of Example 149,1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(1.53 g, 5.11 mmol) was reacted with cyclohexyl isothiocyanate (794 mg,5.62 mmol) to provide 1.35 g ofN-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-N′-cyclohexylthioureaas a tan powder, m.p. 199-200° C. Analysis: Calculated for C₂₃H₃₂N₆OS:%C, 62.70; %H, 7.32; %N, 19.07; Found: %C, 62.37; %H, 7.20; %N, 18.70.

EXAMPLE 158N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-N′-cyclohexylurea

Using the general method of Example 149,1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(1.50 g, 5.01 mmol) was reacted with cyclohexyl isocyanate (780 mg, 5.51mmol) to provide 1.02 g ofN-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-N′-cyclohexylureaas a solid, m.p. 179-180° C. Analysis: Calculated for C₂₃H₃₂N₆O₂.0.75H₂O: %C, 63.06; %H, 7.71; %N, 19.18; Found: %C, 62.74; %H, 7.57; %N,19.16.

EXAMPLE 159N-[4-(4-amino-2-pentyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea

Using the general method of Example 149,1-(4-aminobutyl)-2-pentyl-1H-imidazo[4,5-c]quinolin-4-amine (800 mg, 2.5mmol) was reacted with phenyl isocyanate (0.26 mL, 2.5 mmol) to provide299 mg ofN-[4-(4-amino-2-pentyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylureaas an off white solid, m.p. 159.0-160.4° C. Analysis: Calculated forC₂₆H₃₂N₆O₂.1.0H₂O: %C, 67.51; %H, 7.41; %N, 18.17; Found: %C, 67.73; %H,7.33; %N, 17.97.

EXAMPLE 160N-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea

Part A

Using the general method of Example 146 Part A, tert-butyl4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butylcarbamate was hydrolyzedto provide 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-amine.

Part B

Using the general method of Example 146 Part B,4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-amine (2.50 g, 8.9mmol) was reacted with phenyl isocyanate (1.78 mL, 16.4 mmol) to provide0.67 g ofN-[4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea as anoff white solid.

Part C

Using the general method of Example 146 Part C, material from Part B wasoxidized to provide 604 mg ofN-[4-(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylureaas a yellow residue.

Part D

Using the general method of Example 146 Part D, material from Part C wasaminated to provide 473 mg ofN-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylureaas an off white solid, m.p. 182.8-184.0° C. Analysis: Calculated forC₂₄H₂₈N₆O.1.0 H₂O: %C, 66.34; %H, 6.96; %N, 19.34; Found: %C, 66.69; %H,6.91; %N, 19.37.

EXAMPLE 161N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-N′-phenylurea

Using the general method of Example 149,1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(1.50 g, 5.01 mmol) was reacted with phenyl isocyanate (660 mg, 5.51mmol). Recrystallization from acetonitrile provided 670 mg ofN-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-N′-phenylureaas light orange needles, m.p. ˜40° C. Analysis: Calculated forC₂₃H₂₆N₆O₂.1.0C₂H₃N: %C, 65.34; %H, 6.36; %N, 21.34; Found: %C, 65.13;%H, 6.26; %N, 21.35.

EXAMPLE 162N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-N′-butylurea

Using the general method of Example 149,1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(1.50 g, 5.01 mmol) was reacted with butyl isocyanate to provide 1.13 gofN-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-N′-butylureaas an off-white powder, m.p. 159-160° C. Analysis: Calculated forC₂₁H₃₀N₆O₂.0.29 H₂O: %C, 62.47; %H, 7.63; %N, 20.82; Found: %C, 62.64;%H, 7.58; %N, 21.17.

EXAMPLE 163N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}morpholine-4-carboxamide

Using the general method of Example 143,1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(1.50 g, 5.01 mmol) was reacted with 4-morpholinecarbonyl chloride (830mg, 5.51 mmol) to provide 1.6 g ofN-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}morpholine-4-carboxamideas a white powder, m.p. 194-196° C. Analysis: Calculated for C₂₁H₂₈N₆O₃:%C, 61.15; %H, 6.84; %N, 20.37; Found: %C, 60.82; %H, 6.94; %N, 20.34.

EXAMPLE 164N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea

Using the general method of Example 145, except that the reaction wasrun at ambient temperature,1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.2mmol) was reacted with phenyl isocyanate (0.35 mL, 3.2 mmol) to provide0.75 g ofN-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylureaas white needles, m.p. 185-187° C. Analysis: Calculated for C₂₅H₃₀N₆O.H₂O: %C, 66.94; %H, 7.19; %N, 18.74; Found: %C, 67.31; %H, 7.20; %N,18.70.

EXAMPLE 165N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}morpholine-4-carboxamide

Under a nitrogen atmosphere, triethylamine (1.04 mL, 7.51 mmol) wasadded to a chilled (0°) solution of1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(1.50 g, 5.01 mmol) in chloroform (75 mL). 4-Morpholinecarbonyl chloride(830 mg, 5.51 mmol) was added dropwise. The reaction was allowed to warmto ambient temperature and was maintained over the weekend. An equalvolume of aqueous 1% sodium carbonate was added with vigorous stirring.A precipitate was isolated by filtration to provide 1.73 g of crudeproduct as a white powder. This material was purified by columnchromatography (silica gel eluting with a 0-5% methanol in chloroformgradient) and then triturated with diethyl ether to provide 1.6 g ofN-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}morpholine-4-carboxamideas a white powder, m.p. 194.0-196.0° C. Analysis: Calculated forC₂₁H₂₈N₆O₃: %C, 61.15; %H, 6.84; %N, 20.37; Found: %C, 60.82; %H, 6.94;%N, 20.34.

EXAMPLE 166N-{3-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}morpholine-4-carboxamide

Using the general method of Example 150,1-(3-aminopropyl)-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine(2.0 g, 5.32 mmol) was reacted with 4-morpholinecarbonyl chloride (880mg, 5.86 mmol) to provide 1.8 g ofN-{3-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}morpholine-4-carboxamideas a light yellow crystalline solid, m.p. 198.8-199.9° C. Analysis:Calculated for C₂₇H₃₂N₆O₃%C, 66.37; %H, 6.60; %N, 17.20; Found: %C,66.31; %H, 6.70; %N, 17.40.

EXAMPLE 167N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]morpholine-4-carboxamide

Using the general method of Example 150 except that the reaction was runat 0° C., 1-(3-aminopropyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine(2.0 g, 7.8 mmol) was reacted with 4-morpholinecarbonyl chloride (1.17g, 7.8 mmol) to provide 1.35 g ofN-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]morpholine-4-carboxamideas a white solid, m.p. 226.0-228.0° C. Analysis: Calculated forC₁₉H₂₄N₆O₂: %C, 61.94; %H, 6.57; %N, 22.81; Found: %C, 61.67; %H, 6.46;%N, 22.74.

EXAMPLE 168N-{3-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]propyl}morpholine-4-carboxamide

Using the general method of Example 167,1-(3-aminopropyl)-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 6.59 mmol)was reacted with 4-morpholinecarbonyl chloride (1.08 g, 7.25 mmol) toprovide 1.22 g ofN-{3-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]propyl)morpholine-4-carboxamideas a white powder, m.p. 171.8-173.2° C. Analysis: Calculated forC₂₁H₃₂N₆O₃: %C, 60.56; %H, 7.74; %N, 20.18; Found: %C, 60.30; %H, 7.72;%N, 20.11.

EXAMPLE 169N-3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2,2-dimethylpropyl}-N′-phenylurea

Using the general method of Example 145, 1-(3-amino-2,2-dimethylpropyl)-2-(2-methoxyethyl)-1H-imidazo[4, 5-c]quinolin-4-amine(1.0 g, 3.05 mmol) was reacted with phenyl isocyanate to provide 0.45 gof N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2,2-dimethylpropyl}-N-phenylurea as a white powder, m.p. 125.0-130.0° C.Analysis: Calculated for C₂₅H₃₀N₆O₂. 0.40 H₂O: %C, 66.18; %H, 6.84; %N,18.52; Found: %C, 66.05; %H, 6.61; %N, 18.64. %H₂O calculated: 1.59;found: 1.53 (Karl Fisher);

¹H NMR (300 MHz, DMSO-d₆) δ 8.60 (s, 1H), 8.30 (d, J=8.3 Hz,1H), 7.60(dd, J=8.3, 1.0 Hz, 1H), 7.45-7.36 (m, 3H), 7.26-7.16 (m, 3H), 6.90 (m,1H), 6.58 (s, 2H), 6.52 (m, 1H), 4.81 (br s, 1H), 4.40 (br s, 1H), 3.82(m, 2H), 3.39 (br s, 2H), 3.22 (m, 3H), 0.85 (br s, 6H);

¹³C NMR (125 MHz, DMSO-d₆) δ 155.5, 152.1, 151.5, 144.6, 140.3, 133.4,128.6, 126.3, 126.2, 121.0, 120.9, 120.4, 117.6, 115.3, 70.5, 58.0,51.5, 47.5, 39.5, 27.8, 24.1, 22.6; MS m/z 447 (M+H)

EXAMPLE 170N-[4-(4-amino-2-methyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butyl]morpholine-4-carboxamide

Using the general method of Example 143, 1-(4-aminobutyl)-2-methyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.7 mmol)was reacted with 4-morpholinecarbonyl chloride (0.43 mL, 3.7 mmol) toprovide 1.14 g of N-[4-(4-amino-2-methyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butyl]morpholine-4-carboxamideas an off white solid, m.p. 133.6-134.6° C. Analysis: Calculated forC₂₀H₃₀N₆O₂.1.1H₂O: %C, 59.12; %H, 7.99; %N, 20.68; Found: %C, 58.77; %H,7.53; %N, 20.46.

EXAMPLE 171N-{4-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}morpholine-4-carboxamide

Using the general method of Example 143 except that pyridine was used inplace of chloroform,1-(4-aminobutyl)-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine(1.25 g, 3.2 mmol) was reacted with 4-morpholinecarbonyl chloride (0.41mL, 3.5 mmol) to provide 0.50 g ofN-{4-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}morpholine-4-carboxamide as a light brown solid,m.p. 71.5-72.1° C. Analysis: Calculated for C₂₈H₃₄N₆O₃.0.5H₂O: %C,65.73; %H, 6.90; %N, 16.43; Found: %C, 65.43; %H, 6.90; %N, 16.29.

EXAMPLE 172 N-[4-(4-amino-2-pentyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butyl]morpholine-4-carboxamide hydrochloride

Using the general method of Example 143, 1-(4-aminobutyl)-2-pentyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 4.6 mmol)was reacted with 4-morpholinecarbonyl chloride (0.53 mL, 4.6 mmol) toprovide 1.6 g of the free base form of the named product. This materialwas combined with a minimum amount of methanol. The methanol wasdecanted off from an insoluble residue. The methanol solution wascombined with 1N hydrochloric acid (5 mL) then diluted with diethylether (˜15-20 mL). The solution was concentrated under reduced pressure.The residue was triturated with diethyl ether, isolated by filtrationand then taken up in methanol. The methanol solution was concentratedunder reduced pressure. The residue was dried in a vacuum oven toprovide 1.42 g ofN-[4-(4-amino-2-pentyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butyl]morpholine-4-carboxamidehydrochloride as a light yellow crystalline solid, m.p. 126.8-127.5° C.Analysis: Calculated for C₂₄H₃₈N₆O_(2.HCI.)1.25 H₂O: %C, 57.47; %H,8.34; %N, 16.75; Found: %C, 57.45; %H, 8.07; %N, 16.62.

EXAMPLE 173 tert-butyl3-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate

Part A

3-Chloroperoxybenzoic acid (3.71 g of ˜60%, 13.48 mmol) was added insmall portions over a period of 20 minutes to a solution of tert-butyl3-(1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate (4.0 g, 12.25 mmol) inchloroform (175 mL). After 1 hour the reaction was quenched with aqueousI% sodium carbonate solution. The layers were separated. The organiclayer was washed with aqueous 1% sodium carbonate solution (3×100 mL).The aqueous layer was extracted with chloroform (2×100 mL). The organiclayers were combined and concentrated under reduced pressure to providecrude tert-butyl3-(5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate.

Part B

Using the general method of Example 146 Part D, the material from Part Awas aminated to provide crude product. A small portion (0.5 g) waspurified by recrystallization from acetonitrile to provide 0.22 g oftert-butyl 3-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate asan off white powder, m.p. 196-198° C. Analysis: Calculated forC₁₈H₂₃N₅O₂: %C, 63.32; %H, 6.79; %N, 20.51; Found: %C, 63.05; %H, 6.81;%N, 20.58.

EXAMPLE 174 tert-Butyl3-[4-Amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate

Part A

Using the general method of Example 173 Part A, tert-butyl3-[2-(3-phenoxypropyl)-1H-imidazo[4, 5-c]quinolin-1-yl]propylcarbamatewas oxidized to provide tert-butyl3-[5-oxido-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate.

Part B

Using the general method of Example 146 Part D, the material from Part Awas aminated to provide crude product. A small portion was purified bycolumn chromatography and then recrystallized from acetonitrile toprovide 0.19 g of tert-butyl3-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamateas a tan powder, m.p. 151.0-153.0° C. Analysis: Calculated forC₂₇H₃₃N₅O_(3.)0.25 H₂O: %C, 67.55; %H, 7.03; %N, 14.59; Found: %C,67.54; %H, 6.94; %N, 14.64.

EXAMPLE 175 tert-Butyl3-[4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate

Part A

Using the general method of Example 173 Part A, tert-butyl3-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate wasoxidized to provide tert-butyl3-[2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate.

Part B

Using the general method of Example 146 Part D, the material from Part Awas aminated to provide crude product. A small portion (500 mg) waspurified by column chromatography (silica gel eluting with a 1-10%methanol in chloroform gradient) to provide a solid. This material wasrecrystallized from acetonitrile to provide 150 mg of tert-butyl3-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate as off white plates, m.p. 124.0-126.0°C. Analysis: Calculated for C₂₁H₂₉N₅O₃: %C, 63.14; %H, 7.32; %N, 17.53;Found: %C, 62.87; %H, 7.31; %N, 17.34.

EXAMPLE 176 tert-Butyl 3-(4-Amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate

Part A

Using the general method of Example 173 Part A, tert-butyl3-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate (8.0 g, 23.50mmol) was oxidized to provide tert-butyl3-(2-methyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate.

Part B

Using the general method of Example 146 Part D, the material from Part Awas aminated to provide crude product. A small portion (0.5 g) waspurified by recrystallization from isopropanol to provide 0.15 g oftert-butyl3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate as awhite powder, m.p. 112-115° C. Analysis: Calculated forC₁₉H₂₅N₅O_(2.)1.00 C₃H₈O: %C, 63.59; %H, 8.00; %N, 11.55; Found: %C,63.33; %H, 7.95; %N, 16.70.

EXAMPLE 177 tert-butyl2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate

Part A

Using the general method of Example 173 Part A, tert-butyl2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate (18.2g, 49.1 mmol) was oxidized to provide 17.2 g of tert-butyl2-[2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate as a solid.

Part B

Using the general method of Example 146 Part D, the material from Part Awas aminated to provide ˜18 g of crude product. A small portion waspurified to provide 0.175 g of tert-butyl2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate as a tan powder, m.p. 201.0-202.0° C.MS (CI) m/e 386 (M+H).

EXAMPLE 178 tert-Butyl2-[4-Amino-2-(methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate

Part A

Using the general method of Example 173 Part A, tert-butyl2-[2-(methoxyethyl)-, H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate (19.0g, 51.2 mmol) was oxidized to provide 18.0 g of tert-butyl2-[2-(methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate as a solid.

Part B

Using the general method of Example 146 Part D, the material from Part Awas aminated to provide ˜24 g of crude product. A small portion waspurified to provide 0.218 g of tert-butyl2-[4-amino-2-(methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate as a tan powder, m.p. 173.0-175.0° C.MS (CI) m/e 386 (M+H).

CYTOKINE INDUCTION IN HUMAN CELLS

An in vitro human blood cell system was used to assess cytokineinduction by compounds of the invention. Activity is based on themeasurement of interferon and tumor necrosis factor (α) (IFN and TNF,respectively) secreted into culture media as described by Testerman et.al. In “Cytokine Induction by the Immunomodulators Imiquimod andS-27609”, Journal of Leukocyte Biology, 58, 365-372 (September, 1995).

Blood Cell Preparation for Culture

Whole blood is collected by venipuncture into EDTA vacutainer tubes fromhealthy human donors. Peripheral blood mononuclear cells (PBMCs) areseparated from whole blood by density gradient centrifugation usingHistopaque®-1077 (Sigma Chemicals, St. Louis, Mo.). The PBMCs aresuspended at 3-4×10⁶ cells/mL in RPMI 1640 medium containing 10% fetalbovine serum, 2 mM L-glutamine and 1% penicillin/streptomycin solution(RPMI complete). The PBMC suspension is added to 48 well flat bottomsterile tissue culture plates (Costar, Cambridge, Mass. or BectonDickinson Labware, Lincoln Park, N.J.) containing an equal volume ofRPMI complete media containing test compound.

Compound Preparation

The compounds are solubilized in dimethyl sulfoxide (DMSO). The DMSOconcentration should not exceed a final concentration of 1% for additionto the culture wells.

Incubation

The solution of test compound is added at 60 μM to the first wellcontaining RPMI complete and serial (three fold or ten fold) dilutionsare made. The PBMC suspension is then added to the wells in an equalvolume, bringing the test compound concentrations to the desired range.The final concentration of PBMC suspension is 1.5-2×10⁶ cells/mL. Theplates are covered with sterile plastic lids, mixed gently and thenincubated for 18 to 24 hours at 37° C. in a 5% carbon dioxideatmosphere.

Separation

Following incubation the plates are centrifuged for 5-10 minutes at 1000rpm (˜200×g) at 4° C. The cell culture supernatant is removed with asterile polypropylene pipet and transferred to sterile polypropylenetubes. Samples are maintained at −30 to −70° C. until analysis. Thesamples are analyzed for interferon (α) and tumor necrosis factor (α) byELISA

Interferon (α) and Tumor Necrosis Factor (α) Analysis by ELISA

Interferon (α) concentration is determined by ELISA using a HumanMulti-Species kit from PBL Biomedical Laboratories, New Brunswick, N.J.

Tumor necrosis factor (α) (TNF)concentration is determined using ELISAkits available from Genzyme, Cambridge, Mass.; R&D Systems, Minneapolis,Minn.; or Pharmingen, San Diego, Calif.

The table below lists the lowest concentration found to induceinterferon and the lowest concentration found to induce tumor necrosisfactor for each compound. A “**” indicates that no induction was seen atany of the tested concentrations (0.12, 0.37, 1.11, 3.33, 10 and 30 μM).A “***” indicates that no induction was seen at any of the testedconcentrations (0.0001, 0.001, 0.01, 0.1, 1 and 10 μM).

Cytokine Induction in Human Cells Example Lowest Effective Concentration(μM) Number Interferon Tumor Necrosis Factor 2 0.37 3.33 16 1.11 10 20.37 3.33 4 ** ** 17 ** 30 19 1.11 30 20 1.11 30 21 ** ** 22 ** 10 23 **10 24 ** ** 25 3.33 ** 26 10 ** 27 ** ** 28 1.11 3.33 29 ** 10 30 3.3330 31 ** 10 32 10 10 33 ** ** 34 ** ** 35 1.11 10 36 1.11 10 37 1.11 1038 ** ** 39 1.11 10 40 0.37 3.33 41 1.11 10 42 ** ** 43 ** ** 44 1.11 1045 3.33 ** 46 1.11 3.33 1 3.33 30 47 3.33 10 48 0.37 3.33 49 3.33 3.3350 ** ** 51 30 30 52 1.11 10 6 0.37 ** 5 3.33 ** 67 1 10 69 0.1 1 68 1 1137 1 10 132 0.01 1 133 0.1 10 53 *** 10 54 *** 10 55 1 1 56 1 1 139 ****** 140 10 *** 100 0.001 10 125 0.0001 10 126 0.0001 1 127 0.0001 1 1200.0001 0.01 121 0.01 10 122 0.001 1 71 0.001 1 81 0.01 1 82 0.01 0.1 830.1 1 84 0.1 1 85 0.001 0.1 86 0.1 1 87 1 *** 88 0.1 1 89 0.1 10 1010.01 1 102 0.001 1 103 0.0001 0.1 104 0.0001 1 105 0.001 1 106 0.0001 1107 0.0001 1 108 0.0001 0.0001 109 0.0001 0.1 141 *** 10 110 0.001 1 1110.001 1 112 0.0001 0.1 113 0.0001 1 114 0.0001 0.01 115 0.0001 1 1160.0001 1 117 10 10 118 10 10 119 10 10 142 0.0001 0.1 134 0.001 1 1350.01 10 136 0.0001 1 143 0.01 0.37 144 0.04 0.37 145 0.01 0.04 146 0.010.12 147 0.01 0.12 148 0.04 0.04 149 0.04 0.37 150 0.04 0.37 151 0.010.01 152 0.04 0.04 153 0.01 0.12 154 0.37 1.11 155 3.33 10 156 0.01 1.11157 0.37 1.11 158 0.01 1.11 159 1.11 10 160 0.12 1.11 161 0.01 0.01 1620.01 0.04 163 0.01 0.01 164 0.04 0.12 165 0.01 0.01 169 0.01 0.01 1700.12 10 171 ** 10 172 0.01 0.37 173 1.11 10 174 ** ** 175 0.04 0.37 1760.12 1.11 177 0.04 0.37 178 0.12 1.11

The present invention has been described with reference to severalembodiments thereof. The foregoing detailed description and exampleshave been provided for clarity of understanding only, and no unnecessarylimitations are to be understood therefrom. It will be apparent to thoseskilled in the art that many changes can be made to the describedembodiments without departing from the spirit and scope of theinvention. Thus, the scope of the invention should not be limited to theexact details of the compositions and structures described herein, butrather by the language of the claims that follow.

What is claimed is:
 1. A compound of the formula (I):

wherein bonds represented by dashed lines are present or absent; R₁ is—C₂₋₆ alkyl-NR₃—CY—NR₅—R₄ wherein Y is ═O or ═S; R₄ is hydrogen, alkyl,aryl, or substituted aryl; R₂ is selected from the group consisting of:-hydrogen; -alkyl; -alkenyl; -aryl; -substituted aryl; -heteroaryl;-substituted heteroaryl; -alkyl-O-aryl; -alkyl-O-alkyl;-alkyl-O-alkenyl; and -alkyl or alkenyl substituted by one of moresubstituents selected from the group consisting of: —OH; -halogen;—N(R₃)₂; —CO—N(R₃)₂; —CO—C₁₋₁₀ alkyl; —CO—O—C₁₋₁₀ alkyl; —N₃; -aryl;-substituted aryl; -heterocyclyl; -substituted heterocyclyl; —CO-aryl;—CO-(substituted aryl); —CO-heteroaryl; and —CO-(substitutedheteroaryl); each R₃ is independently selected from the group consistingof hydrogen and C₁₋₁₀ alkyl; R₅ is selected from the group consisting ofhydrogen and C₁₋₁₀ alkyl, or R₄ and R₅ can combine to form a 3 to 7membered heterocyclic or substituted heterocyclic ring; n is 0 to 4 andeach R present is independently selected from the group consisting ofC₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, halogen and triflutoromethyl, or apharmaceutically acceptable salt thereof.
 2. A compound of claim 1wherein the dashed bonds are absent.
 3. A compound of claim 2 wherein Yis ═O.
 4. A compound of claim 2 wherein n is
 0. 5. A compound of claim 2wherein R₃ is hydrogen.
 6. A compound of claim 2 wherein R₂ is selectedfrom the group consisting of hydrogen, C₁₋₄alkyl, andC₁₋₄alkyl-O—C1-4alkyl.
 7. A compound of claim 2 wherein R₄ and R₅combine to form a 3 to 7 membered substituted or unsubstitutedheterocyclic ring.
 8. A compound selected from the group consisting of:N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea;N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea;N-{8-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]octyl}-N′-phenylurea;N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-phenylurea;N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-phenylthiourea;N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N-butylurea;N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]morpholine-4-carboxamide;N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-propylthiourea;N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-cyclohexylurea;N-[8-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)octyl]-N′-phenylurea;N-[4-(4-amino-2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea;N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-propylthiourea;N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-cyclohexylthiourea;N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-cyclohexylurea;N-[4-(4-amino-2-pentyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-N′-phenylurea;N-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-N′-phenylurea;N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-N′-phenylurea;N-3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-N′-butylureaN-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}morpholine-4-carboxamide;N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea;N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}morpholine-4-carboxamide;N-{3-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}morpholine-4-carboxamide;N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]morpholine-4-carboxamide;N-{3-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]propyl}morpholine-4-carboxamide;N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2,2-dimethylpropyl}-N′-phenylurea;N-[4-(4-amino-2-methyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butyl]morpholine-4-carboxamide;N-{4-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}morpholine-4-carboxamide;andN-[4-(4-amino-2-pentyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butyl]morpholine-4-carboxamide;or a pharmaceutically acceptable salt thereof.
 9. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1 in combination with a pharmaceutically acceptable carrier.10. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 2 in combination with a pharmaceuticallyacceptable carrier.
 11. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 8 in combinationwith a pharmaceutically acceptable carrier.
 12. A method of inducingcytokine biosynthesis in an animal comprising administering atherapeutically effective amount of a compound of claim 1 to the animal.13. A method of inducing cytokine biosynthesis in an animal comprisingadministering a therapeutically effective amount of a compound of claim2 to the animal.
 14. A method of inducing cytokine biosynthesis in ananimal comprising administering a therapeutically effective amount of acompound of claim 8 to the animal.
 15. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound of theformula Ia:

wherein bonds represented by dashed lines are present or absent; R₁ is-alkyl-NR₃—CO—O—R₄; R₄ is alkyl, aryl, or substituted aryl; R₂ isselected from the group consisting of: -hydrogen; -alkyl; -alkenyl;-aryl; -substituted aryl; -heteroaryl; -substituted heteroaryl;-alkyl-O-aryl; -alkyl-O-alkyl; -alkyl-O-alkenyl; and -alkyl or alkenylsubstituted by one or more substituents selected from the groupconsisting of: —OH; -halogen; —N(R₃)₂; —CO—N(R₃)₂; —CO—C₁₋₁₀ alkyl;—CO—O—C₁₋₁₀ alkyl; —N₃; -aryl; -substituted aryl; -heteroaryl;-substituted heterocyclyl; —CO-aryl; —CO-(substituted aryl);—CO-heteroaryl; and —CO-(substituted heteroaryl); each R₃ isindependently selected from the group consisting of hydrogen and C₁₋₁₀alkyl; n is 0 to 4 and each R present is independently selected from thegroups consisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, halogen andtrifluoromethyl; or a pharmaceutically acceptable salt therefore incombination with a pharmaceutically acceptable carrier.
 16. Apharmaceutical composition of claim 15 wherein the compound is selectedfrom the group consisting of: tert-butyl3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate;tert-butyl3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate;tert-butyl 3-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate;tert-butyl3-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate;tert-butyl3-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate;tert-butyl3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate;tert-butyl3-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate;and tert-butyl3-[4-amino-2-(methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate.17. A method of inducing cytokine biosynthesis in an animal comprisingadministering a therapeutically effective amount of a composition ofclaim 15 to the animal.
 18. A method of inducing cytokine biosynthesisin an animal comprising administering a therapeutically effective amountof a composition of claim 16 to the animal.